LONG TERM OUTCOMES AFTERALLOGENEIC HSC TRANSPLANTATION

FOR FANCONI ANEMIA

John E. Wagner, M.D.

Division Blood and Marrow Transplantation University of Minnesota

Bone Marrow Failure Scientific SymposiumAplastic Anemia and MDS Society

18 March 2016

Fanconi AnemiaVariable Phenotype

• Skin (café au lait) 71%• Radial Ray 59%• Kidney/urinary 57%• Short stature 67%• Ears/deafness ?• CNS 1%• Eyes 47%• GI (esoph, duod) 7%• Cardiac (PDA/VSD) 29%

‘Classic’ phenotype – missing thumb, missing kidney, short and bone marrow failure

V – vertebral fusionsA – anal atresiaC – cardia (PDA and VSD)TE – tracheoesophageal fistulaR – renal (hydronephrosis)/radial defectsL – Limb (non radial) defects

Long-Term Survival in FA Non-Hematologic Manifestations of the

Disease

Side effects from surgeries- Esophageal dilations after TE fistula repair- Impactions after anal atresia repair

State of the Art-1995 Survival in FA Patients by Donor Type

IBMTR Blood 1995, 97: 633

Years

0.0

0.2

0.4

0.6

0.8

1.0

0 1 2 3 4

Unrelated Donor BMT

Sibling Donor BMT Deliberate conception

If no sibling donor, then delayed transplant

- RAEBt / AML - heavily transfused

PGD to prevent disease and save the life of an existing child

PGD for mutation PGD

for HLA

To eliminate risk of genetic

disease

To create an HLA identical

stem cell donor

Risk factors: Acute / Chronic GVHD Use of azathioprine Radiation (?)

Disproportionately Higher Cancer Risk in FA after BMT

Deeg HJ et al. Blood 1996; 87:386-392

Matched Sibling Donor BMT for FATrial 1 - CY, ATG, TLI 450Trial 2 - CY, ATG, FLU, TCD

Cum

ulat

ive

prop

ortio

n

Months after HSCT

0.0

0.2

0.4

0.6

0.8

1.0

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

97%n=28

• 100% engraftment• 0% severe RRT• 3% acute GVHD• 0% chronic GVHD

Matched Sibling Donor BMT for FA Improved Survival

Unrelated Donor BMT for FA

Unrelated Donor BMT for FA Improved Survival

Years after HCT

Cum

ulat

ive

Prop

ortio

n

P < 0.01

0.0

0.2

0.4

0.6

0.8

1.0

0 1 2 3 4 5

IIII

IIIII

IIIIIIIIIIIIIIIIIIIIII

IIIIIIIIII

I I I IIII II I I I II I I I

I I I III IIIIII

2006-2012 [73%]

2003-2006 [63%]

1999-2003 [51%]

1982-1995 [50%]

1995-1999 [22%]

MacMillan M et al. Blood 2015; 125:3798-3804

• Radiation (dose dependent)– Cataracts– Infertility (50% females; 100% males infertile

without transplant)– Pulmonary– Cancer – thyroid, other?

• Busulfan (exposure dependent)– Hepatic (VOD)– Infertility (as above)– Pulmonary– Cancer

• Cyclophosphamide– Hemorrhagic cystitis– Cancer ?

What do we know? BMT specific late effects

- Reduced dose 450, 300, 150 cGy

- Shielding

- PK (targeted exposure)

- Reduced dose

• Cyclosporine A– Nephrotoxicity (transient vs permanent)

• Methylprednisolone– Insulin resistance (likely transient)– Osteonecrosis

• Antibiotics– Nephrotoxicity (Foscarnet, aminoglycosides)– Ototoxicity (aminoglycosides)– Cancer (KGF, Voriconazole)

• Other drugs– ATG, MMF, MTX, Fludarabine, ARA-C

(unlikely to have long-term effects)

What do we know? BMT specific late effects

- Sirolimus / MMF

- Eliminated

- Reduced exposure

• Acute GVHD (and its therapy)– Opportunistic infection (Immune dyregulation)– End-organ damage (renal, osteonecrosis, osteopenia)– Cancer

• Chronic GVHD (and its therapy)– Opportunistic infection (Immune dyregulation)– End-organ damage (renal, osteonecrosis, osteopenia)– Growth failure (malabsorption)– Cancer

• Slow immune reconstitution– Opportunistic infection– Cancer

What do we know? BMT specific late effects

- T cell depletion

- Thymic shielding

Endocrinopathies after BMT Over 80% of FA patients have at least one

abnormal endocrine test

• Hypothyroidism (60%)• Short stature with or without growth hormone

deficiency (50%)• Gonadal hormone deficiency (65%)• Lipid abnormalities (55%)• Abnormal glucose and insulin metabolism (45%)• Low bone mineral density (high, study in progress)

Dr Anna PetrykUniversity of Minnesota

Other factors

• Hemochromatosis (abnormal Fe metabolism, transfusions)– Effects on testicular, thyroid, pituitary function, and contributes

to diabetes

• Androgen therapy– Insulin resistance– Premature closure of growth plates

Cancer RiskIncidence 30% by age 45 years

Observed to Expected Ratio

• Head/Neck 706

• Esophagus 2362

• Liver 386

• Total 50Rosenberg PS, et al.

Blood 2003; 101: 822–826.

Alan D’Andrea. The Fanconi anemia and breast cancer susceptibility pathways. N Engl J Med 2010; 362: 1909-19.

FA-A 60%

FA-C 14.8%

FA-G 9%

Downstream FactorsFA-D1(BRCA2)

FA-J (helicase)

FA-N (helicase)

FA-O (RAD51C, HR)

FA-P (scaffold for nucleases)

FA-Q (NT excision repair)

FA-S (BRCA1)

RAD51

Core ComplexFA-A, B, C, E, F, G, L, M

Central FactorsFA-D2 and I

Binds DNA Structure, exonuclease activity

BRCA2 and Leukemia

BRCA2 n=14

FA C n=78 FA A+G n=253

Other FA n=415

All occurred before age of 6 years

High risk of other malignancy before and after HSCT

Potential impact of GVHD on Cancer Risk

Guardiola P et al. Blood 2004; 103:7-77

Chronic GvHD among FA patients University of Minnesota (n=234)

Months after BMT

Cum

ulat

ive

Inci

denc

e

Alternative donorMatched sibling

P = 0.24

0.0

0.2

0.4

0.6

0.8

1.0

0 3 6 9 12 15 18 21 24

CD34 selectionCsAMMFATG in conditioning

Cancer Risk in Fanconi Anemia Risk after BMT

Cum

ulat

ive

Inci

denc

e

Years of Age

0.0

0.2

0.4

0.6

0.8

1.0

0 5 10 15 20

13% (2-24%) at 20 years after BMT

19% (7-31%) by age 45 years

Cancer Risk in Fanconi Anemia Risk by Patient Age

Years of Age

0.0

0.2

0.4

0.6

0.8

1.0

0 5 10 15 20 25 30 35 40 45

Cum

ulat

ive

Inci

denc

e

Fanconi Anemia Survival is dismal after cancer diagnosis

29% (1-70%) 0.0

0.2

0.4

0.6

0.8

1.0

0 12 24 36 48 60

Months after BMT

Cum

ulat

ive

Inci

denc

e

Intolerance to DCL agents [particularly in non transplanted patients]

No systematic evaluation or treatment plan

Wish ListEliminate DCL agents

- Busulfan (pharmacokinetics)- TBI (alternative: dose reduce and shield)

Ask for a sibling donor- HLA matched / disease free

Enhance lympho-hematopoietic recovery

Enhance Lympho-Hematopoietic Recovery

Days after BMT

Cum

ulat

ive

Inci

denc

e

Alternative donor

Matched sibling donor

0.0

0.2

0.4

0.6

0.8

1.0

0 7 14 21 28 35 42

UCB

Eapen et al. Lancet Oncol 2010; 11: 653-60

Adults

Eapen et al. Lancet 2007; 369:1947-54

Children

Limiting numbers of HSPCs in UCB: The Obstacle

CD34+ Cell

Growth factor

receptors

Differentiation

AhR

AhRL

SR-1

XRE

Nucleus

AhRL

CYP1B1/AHRR

Cytosol

• SR-1 was identified in a screen of compounds that promoted CD34/CD133 expansion

• AhR inhibition blocks HSC differentiation in presence of stimulatory cytokines (retinoic pathway)

• SR-1 AhR inhibition is reversible

StemRegenin-1 (SR-1) is aryl hydrocarbon receptor antagonist

Boitano et al. Science 2010; 1345-1348

N

N

N

N

HN

OH

S

SR-1

0 200 400 600 800 1000 1200 1400 1600

Pre Cryo

CD34+

SF6T + SR1

CD34-

Total CD34+ (x106) Before and After Selection and Expansion Culture

100-fold expansion of CD34+/133+/90+ population

Neutrophil Recovery Myeloablative Conditioning

Wagner et al. Unpublished data

Conclusion with HSC8351. Expansion culture with SF6T + SR-1 leads to 350-fold

increase in the CD34+ cells with both short and long-term engraftment potential

2. Duration of neutropenia is dramatically shortened with engraftment in all patients

3. Neutrophil recovery correlates with CD34+ cell dose

4. Intriguing possible uses: expansion of HSC in BM aspirates expansion of gene corrected HSC manufacture of thymic progenitors

Wish ListDevelop central registry

- tissue banking (blood, marrow, fibroblasts)- clinical outcome data to evaluate interventions

Cancer consortium- Detailed treatment plan and data/sample collection

Take Home Message• Long term survival is the expectation after

BMT for bone marrow failure and MDS in children and young adults

• Cancer is the greatest barrier to longer term survival

• Centralized data and sample repositories are needed to understand

University of Minnesota BMT Program

Pediatric BMT

Mukta Aurora, M.D. Veronica Bachanova, M.D.Nelli Bejanyan Claudio Brunstein, M.D.Sarah Cooley, M.D. Dan Kaufman, M.D., Ph.D.Brian McClune, D.O. Philip McGlave, M.D. Jeffrey Miller, M.D. Arne Slungaard, M.D. Celalettin Ustun, M.D. Greg Vercelotti, M.D. Erica Warlick, M.D. Dan Weisdorf, M.D.

Bruce Blazar, M.D. Christen Ebens, M.D. Keli Hippen, Ph.D. Margaret MacMillan, M.D.Wes Miller, M.D. Angela Mortari, Ph.D. Paul Orchard, M.D. Jakub Tolar, M.D., Ph.D. Angela Smith, M.D. Heather Stefanski, MD, Ph.D. Michael Verneris, M.D. Todd Defor, M.S.

(Statistical Section)

Adult BMT

Novartis TeamTony Boitano, Ph.D. Michael Cooke, Ph.D. Conrad Bleul, M.D.