Farid Boulad, M.D....Bertaina A – Locatelli F, et al. Blood 2014. HSCT FOR FANCONI ANEMIA The last...
Transcript of Farid Boulad, M.D....Bertaina A – Locatelli F, et al. Blood 2014. HSCT FOR FANCONI ANEMIA The last...
HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR THE TREATMENT OF FANCONI ANEMIAFOR THE TREATMENT OF FANCONI ANEMIA
Haploidentical Donor HSCT
Bone Marrow Failure Disease Scientific SymposiumMarch 17 & 18, 2016 – Hilton Rockville,
Farid Boulad, M.D.
I h it d B M F il S d
FANCONI ANEMIA• Inherited Bone Marrow Failure Syndrome• Chromosomal Breakage Disorder - DNA repair defect
• Rare - Number of patients ~ 3,000-4,000
• Mostly autosomal recessive disease (rarely X-linked)• Mostly autosomal recessive disease (rarely X-linked)
• Genetically and phenotypically heterogeneous disease
• Clinical characteristics– Multiple congenital abnormalities– Endocrinopathies– Bone marrow failure (AA)– Hematologic Cancer susceptibility (MDS-AML)– Epithelial Cancer susceptibility / predisposition
FANCONI ANEMIAHEMATOLOGIC ABNORMALITIES
• Median Age at Diagnosis: 7 years (range 0-50+ years)
• Hematologic abnormalities:Macrocytosis - ↓ Plts - ↓ Hgb - ↓ WBC ↓ BM C ll l it A l ti A i (AA)↓ BM Cellularity – Aplastic Anemia (AA)
• Hematologic Complications AA MDS/AMLg pActuarial risk: by age 10 73% 7%
by age 20 - - 27% by age 40 98% 33-52%by age 40 98% 33-52%
Cytogenetic abnormalities: chromosomes 1 3 and 7chromosomes 1, 3 and 7
Rosenberg et al. – Kutler et al. Blood 2002
FANCONI ANEMIATHERAPEUTIC OPTIONS
• Supportive Care • AndrogensAndrogens • Hematopoietic Growth Factors• Transfusions
• Allogeneic Stem Cell Transplantation– Based on: Hematologic diagnosis: SAA – MDS – AMLg g
Donors: Matched Related – Alternative donors
• Gene Therapy– FANC A and FANC C
Di i F t
FA - Hematologic Stages - ComplicationsDiagnosis Features
Single Lineage Cytopenia One lineage low: ANC < 0.5 or Hgb < 8 or Plts < 20,000
Moderate Aplastic Anemia At least 2 lineage cytopenias Transfusion INdependent Bone Marrow Hypocellular
Severe Aplastic Anemia Two lineage cytopenias Transfusion Dependent Bone Marrow Hypocellular
Low risk MDS
1 or more lineage cytopeniaBone marrow DYSmorphology Low risk chromosome abnormality (Chr 1) Bone marrow: Blasts < 5% 1 or more lineage cytopenia
High Risk MDS
1 or more lineage cytopeniaBone marrow DYSmorphology High risk chromosome abnormality (Chr 3 or 7) Bone marrow: Blasts 0-20%
AML Bone marrow: Blasts >20%
Fanconi anemia – HSCTTransplant IndicationsTransplant Indications
Allogeneic stem cell transplantation is indicated in all patients with Fanconi anemia who develophematologic complications that include:
- Severe Single Lineage Cytopenias (+/- Androgen trial)
- Severe Aplastic Anemia (+/- Androgen trial)Severe Aplastic Anemia (+/- Androgen trial)
- High Risk Myelodysplastic Syndrome- Acute Myelogenous Leukemiay g
Early HSCT ResultsFanconi anemia – HSCT
Early HSCT ResultsHLA-matched related donors
Eliane Gluckman et alEliane Gluckman et al.
•1980 – HSCT for 5 patients with FA - One patient survivedU i Hi h D TBI C l h h idUsing High Dose TBI – Cyclophosphamide
•1980: Hypersensitivity of FA patients to cyclophosphamide•1980: Hypersensitivity of FA patients to cyclophosphamide•1983: Hypersensitivity of FA patients to radiation
•1984-1990: N= 19 patients - Conditioning Regimen incl.Low dose ThoracoAbdominal RT (500 cGy)Low dose Cyclophosphamide (20 mg/Kg)OS: 74% - GvHD 58%
Fanconi anemia – HSCTLow dose TBI/TAI – Low dose Cy
CIBMTR - 1995
Gluckman et al. Blood 1995
Fanconi anemia – HSCTLow dose TBI/TAI – Low dose CyLow dose TBI/TAI Low dose Cy
EBMT 1972-1999
R. Peffault de Latour, C Dufour, et al. Blood 2013
100% 100%NMDP – N=58O ll S i l
Fanconi anemia – Unrelated donor HSCT
60%
70%
80%
90%
val
60%
70%
80%
90%Overall Survival 1995–2003
20%
30%
40%
50%
Surv
i
20%
30%
40%
50%
OS = 34%
0%
10%
0 1 2 3 4 5
Years After Transplant
0%
10%
The ability to perform SCT for the treatment of patients with FA, usingalternative donors with cytoreductive regimens standardly used for FA hadbeen limited by increased risks of:
- Graft rejection / failure 17-35%- Acute and chronic GvHD > 50%- Peri-transplant toxicity 10-20%- Peri-transplant toxicity 10-20%- Infections 10-20%DFS: ~ 30%
Fanconi anemia – HSCTPost Fludarabine Era
J Wagner, M Eapen, et al. Blood 2007
Fanconi anemia – HSCTPost Fludarabine EraPost Fludarabine Era
EBMT 2013
R Peffault de Latour, C Dufour et al. - Blood 2013
Allogeneic hematopoietic stem cell transplantation in Fanconianemia: the European Group for Blood and Marrowp pTransplantation (EBMT) experience.
We analyzed results in 795 patients with FA who underwent… We analyzed results in 795 patients with FA who underwentfirst HSCT between May 1972 and January 2010. With a 6-yearmedian follow-up, overall survival was 49% at 20 years. Better
t b d f ti t t l t d b f thoutcome was observed for patients transplanted before theage of 10 years, before clonal evolution (ie, myelodysplasticsyndrome or acute myeloid leukemia), from a matched familyy y ) ydonor, after a conditioning regimen without irradiation, thelatter including fludarabine.
Ch i f h di d dChronic graft-versus-host disease and secondarymalignancy were deleterious when considered as time-dependent covariates...p
R Peffault de Latour, C Dufour, et al. Blood 2013
Fanconi anemia – HSCTThe Curitiba experience
HLA Matched Siblings 5 year OS 93 % (N=56)
N=122HLA Matched Siblings 5 year OS 93 % (N=56)
Alternative donors : 5 year OS =86% (N=66)
Matched related donors: CY 60
Carmem Bonfim - Data from Curitiba – Brazil 2015
Unrelated donors: CY 60 + FLU + ATG
HSCT FOR FANCONI ANEMIASTRATEGY FOR OPTIMIZATION OF SCT
1. Addition of FLUDARABINE to the standard cytoreductive regimen to increase the immunosuppression
FOR FA USING ALTERNATIVE DONORS
to increase the immunosuppression → Decrease risk of graft rejection→ No added organ toxicity
2. The use of G-CSF mobilized PBSC (instead of BM) whenever possible to increase the number of stem cells (2-20 fold) (Megadose)
→ Decrease risk of graft rejection
3. The use of T–CELL DEPLETION of the graft → Decrease risk of GvHD
4. Add Tacrolimus/Cyclosporine to regimen of ATG→ Decrease risks of GvHD and graft rejection
5 Add G-CSF to regimen to promote engraftment5. Add G CSF to regimen to promote engraftment→ Decrease the risks of graft rejection
AltD HSCT FOR FANCONI ANEMIADONOR PREFERENCE T cell depleted SCTDONOR PREFERENCE – T-cell depleted SCT
HLA t hi D l ti S f t llHLA matching Donor relation Source of stem cells
8/8 Related PBSC or BM7/8 R l t d PBSC BM7/8 Related PBSC or BM8/8 Unrelated PBSC or BM7/8 Unrelated PBSC or BM7/8 Unrelated PBSC or BM
4-6/8 Related PBSC or BM7/8 Unrelated UCB
VS7/8 Unrelated UCB
4-6/8 Unrelated UCB
G-CSF 6 mcg/Kg/dose BID SCDONOR
IRB 01-062
G-CSF 6 mcg/Kg/dose BID SC
PBSC Collection
CD34+ E tti
PATIENT
CD34+ E-rosetting
SD TBI Flu Flu Flu Flu Flu
CD34+E-T-cell depleted
PATIENT
TBI 450 cGy CY CY CY CY
Flu Flu Flu Flu Flu T cell depletedPBSCT
-7 -6 -5 -4 -3 -2 -1 0ATG ATG ATG ATG
Start Tacro
G-CSF
Steroids
Start Tacro
Fanconi anemia – HSCTAlternative Donors
MSKCC N 24
Acute and Chronic GvHD
MSKCC N=24
0.8
0.9
1Acute and Chronic GvHD
0.5
0.6
0.7
rtio
n
0.2
0.3
0.4
GvHD 9 6%
Prop
or
0
0.1
0 20 40 60 80 100 120
GvHD 9.6%
Time post transplant (Months)
S Chaudhury, F Boulad, et al. Brit J Haematol. 2008
IRB 08-031
G-CSF 10 mcg/Kg/dose Daily SCPBSC Collection
DONOR
PATIENT
CD34+ selection/T cell depletion
CD34+
PATIENTBU PK studies
CY CY CY CY
Flu Flu Flu Flu PBSCT
BU BU
studies
-8 -7 -6 -5 -4 -3 -2 -1 0ATG ATG ATG ATG
G-CSF
Steroids
Start CSA
Fanconi anemia – HSCTAlternative Donors
Multi-institutional Study of Chemotherapy-only Preparative Regimen forAlternative Donor Hematopoietic Cell Transplantation for Patients with FA
DFS = 82%
N = 45
P Mehta, S Davies, F Boulad, et al. Manuscript in preparation
Fanconi anemia – HSCTAlternative Donors
Multi-institutional Study of Chemotherapy-only Preparative Regimen forAlternative Donor Hematopoietic Cell Transplantation for Patients with FA
No difference in outcome for:- SAA and MDS- Prior Androgens- Prior RBC or PLT transfusions
GvHDGrade 3 4 None- Grade 3-4 None
- Chronic limited 3
P Mehta, S Davies, F Boulad, et al. Manuscript in preparation
HSCT FOR FANCONI ANEMIAUnrelated Donors
1.0
Unrelated DonorsMSKCC N=26
0.8Matched
DFS = 83.3% (N=12)
0.6
port
ion
Mismatched DFS = 57.1% (N=14)
0.4
Prop
Matched 10/10 all SAA N=8S
0.0
0.2 MDS-AML N=4Mismatched 9/10 N= 8
8/10 N= 6SAA N=7MDS-AML N=7
0 6 12 18 24Time Post Transplant (months)
HSCT FOR FANCONI ANEMIAMismatched Related Donors
1.0
Mismatched Related Donors
0.8
DFS = 61 5% (N=13)0.6
opor
tion
DFS = 61.5% (N=13)
0.4
Pro
0.2
0.00 6 12 18 24
Time Post Transplant (months)
HSCT FOR FANCONI ANEMIAMismatched Related Donors
Unmodified BMT – Post transplant CYWisconsin - Seattle – Curitiba protocol
Unmodified BMT Post transplant CY
Thakar et al Pediatr Hematol Oncol. 2012
HSCT FOR FANCONI ANEMIAMismatched Related Donors
T-cell depleted HSCT – αβ T-cell + CD19 B-cell depletion
Bertaina A – Locatelli F, et al. Blood 2014
HSCT FOR FANCONI ANEMIAMismatched Related Donors
T-cell depleted HSCT – αβ T-cell + CD19 B-cell depletion
Bertaina A – Locatelli F, et al. Blood 2014
HSCT FOR FANCONI ANEMIAThe last 4 decades
HLA Matched
Sibs
HLA Matched
Sibs
HLA Matched
Sibs
HLA Matched
Sibs
UnrelatedDonors
UnrelatedDonors
UnrelatedDonors
MismatchedRelatedDonors
MismatchedRelatedDonors
Low dose CY Low dose CY + Fludarabine αβ T-cell depletion
Low dose TBI/TAI Low dose TBI/TAI T-cell depletion Post Transplant CY
Fanconi anemia – Haploidentical Donor HSCTSUMMARY (1)
1. Hematopoietic HSCT for patients with Fanconi anemia using Haploidentical donors can be performed using
( )
g p p g• a T-cell depleted marrow or peripheral blood stem cell graft
using a CD34+ selection or T-and B- selection• a Fludarabine – Cyclophosphamide – ATG based• a Fludarabine – Cyclophosphamide – ATG based
cytoreduction with minimal risks of graft rejection and GvHD.
2. Post transplant Cyclophosphamide approach can also be performed with good outcome but may be associated with p g yhigher risk of GvHD.
3 Remaining problematic issues that need to be solved3. Remaining problematic issues that need to be solved include: Infections - Organ toxicity - Relapse
Fanconi anemia – Haploidentical Donor HSCTSUMMARY (2)
3. Our next strategy is to solve the problematic issues
( )
-Infections- αβ T-cell depletion or γδ T-cell reinfusion- Specific Cytotoxic T-cell prophylaxisSpecific Cytotoxic T cell prophylaxis
-Toxicity? T lf- ? Treosulfan
- Keratinocyte Growth Factor (need in-vitro data re: safety)
-Relapse- Use of Hypomethylating agents pre- or post- HSCT- Pre-transplant low dose chemotherapy prior to HSCTPre transplant low dose chemotherapy prior to HSCT
CENTER FOR THE STUDY OF GENETIC DISORDERS OF HEMATOPOIESIS
THANKSPatients and familiesFARF
- Blanche Alter- Carmem Bonfim
Yigal Dror
Our MSKCC team
- Yigal Dror- Carlo Dufour- Wolfram Ebell
- Alfred Gillio
- Eliane Gluckman- Helmut Hanenberg
Richard Harris- Arleen Auerbach- Agata Smogorzewska
- Richard Harris- Margaret MacMillan- Akiko Shimamurag g
- Eva Guinan- Parinda Mehta
- Jakub Tolar- John Wagner
- Stella Davies