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