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.