UAB Symposium Congenital Bone Marrow Failure Path to Cure

Transcription

1 UAB Symposium Congenital Bone Marrow Failure Path to Cure

2 Patient s Journey 8 yo male Generally healthy Short stature (5%ile) Hypermobile thumbs with flattened thenar eminences Hair and nails normal 1 year history of low platelet counts

3 Referral to Hematologist CBC worsened over the year Test Result Normal Range WBC 2.7 x 10*9/L ANC 1.8 x 10*9/L Hgb 13.8 g/dl MCV 103 fl Plt 54 x 10*9/L

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5 Diamond Blackfan Anemia Interconnected Pathways of Congenital BMF Disorder of ribosomal proteins Fanconi Anemia Dyskeratosis Congenita Disorder of proteins that maintain telomers Disorder of DNA repair

6 Diagnostic Mutagen Stress Test

7 Classic Manifestations of Fanconi Anemia Can effect every organ in the body 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

8 Effect of Incorrect Diagnosis V Vertebral fusions A Anal atresia C Cardiac (PDA and VSD) TE Tracheo-Esophageal fistula R Renal (hydronephrosis)/radial defects L Limb (non radial) defects Devastating Effects - No surveillance for MDS/leukemia - Incorrect reproductive counseling (or evaluation of existing siblings)

9 When to test for FA Absolute indications for DEB testing - aplastic anemia (any age) Possible indications for DEB testing - young patient with H/N cancer - MDS with complex cytogenetic abnormalities - constellation of macrocytic anemia, short stature - VATER/VACTERL (don t be swayed by prior dx)

10 FA VATER Signature Higher frequency of renal and limb (radial and/or thumb) anomalies 93% in FA VATER <30% in non FA VATER Skewed distribution within FA FANCB (21%) FANCD1/BRCA2 (14%) FANCD2 (12%) FANCA (19%) Recommendation All VATER patients with renal and limb anomalies, then test for FA

11 General Pattern of Bone Marrow Failure

12 Complex Cytogenetic Abnormality Clone 1 ISCN: 46,XY,dup(1)(q12q32)[9]/46,XY, del(20)(q11.2q13.3)[10]/46,xy[1] INTERPRETATION: Two abnormal clones were identified. Clone 1, comprises 45% of metaphases; duplication within the long arm of chromosome 1, extending from band q12 to q32. Clone 2, comprises the remaining 55% of metaphases, had a deletion within the long arm of chromosome 20, extending from band q11.2 to q13.3.

13 Impact of Overriding the G2/M Arrest Clonal Chromosomal Abnormalities Percent qG 7pL/7qL 1qG 6pL 7pL 7qL 11qL 1pL 6qL 17pL Betsy Hirsch, Ph.D.

14 Evolution of Clonal Chromosomal Abnormalities 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 3qG -7/7qL 1qG With "other" abnl With 1qG, 3qG or 7qL Sole abnormality What do they mean? More frequent marrow exams Betsy Hirsch, Ph.D.

15 ~16% do not have BMF, MDS or Acute Leukemia by age 18 years

16 Pathophysiology of BMF, MDS and Acute Leukemia in FA Oligoclonal hematopoiesis - marrow failure - MDS / leukemia (evading G2/M arrest) DNA damage Viral suppression [INFg hypersensitivity]

17 FA/BRCA DNA Repair Path FA-A 60% FA-C 14.8% FA-G 9% Autosomal Recessive (except FA-B) BRCA2 Unique issues - impact on carriers - genetic testing in children who are potential donors The Fanconi Anemia Pathway of DNA Repair and Human Cancer By Vaidehi Krishnan, Lavina Sierra Tay and Yoshiaki Ito

18 Genotype / Phenotype Correlations Time to MDS or Leukemia FANCD1/BRCA2 n=14 All <7 years of age High risk of other malignancies before and after HSCT FANCC n=78 Other FANC Groups n=415 FANCA+G n=253

19 FANCC Genotype-Phenotype Correlations Onset of Marrow Failure Survival Non FANCC FANCC exon 1 FANCC exon 1 Non FANCC FANCC exon 14 FANCC IVS4 FANCC IVS4 FANCC exon 14 Gillio AP, Verlander PC, Batish SD, Giampietro PF, Auerbach AD. Blood 1997;90:

20 Indications for HSC Transplant Severe cytopenia o Hgb <8 g/dl o ANC <500/mm 3 o PLT <20,000/mm 3 MDS/Leukemia

21 Eligibility Requirements Adequate organ function o Renal (GFR >30) o Liver (ALT <3 x normal) o Cardic (EF >45) Available donor o Sibling BM (without FA) o Unrelated BM o Unrelated UCB o Haplo BM

22 Conditioning Dilemma in FA TBI 450 rather than 1200 cgy Cyclophosphamide 40 rather than 200 mg/kg ATG T cell depleted HSC Myeloablation Destroy Leukemia and the Host s Immune System Principles Immunosuppression Prevention of HVG and GVH reactions CSA

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

24 State of the Art Sibling Donor Transplants after Complications are rare except in those with MDS/Leukemia or adult age Years

25 Unrelated Donor BMT for FA

26 Thymus Shielding Prior to HCT, CT is performed to locate the thymus Thymus block Thymus blocks attached to TBI stand brackets securing the lung compensators

27 Perserving Fertility Transient Transposition of the Ovary

28 Survival in FA Patients Unrelated Donors Cumulative Proportion I FLU CY TBI (300) + TS 89% I I II I I I II I III I I I III FLU CY TBI (450) + TS 75% I I I I I I I I I I I I I I I I I I I I FLU CY TBI (450) 67% CY TBI (450) 23% Years

29 Alternative Donor BMT for FA Survival Risk Factors Effect of Transfusions Effect of Infection History Androgens negative effect in univariate analysis (trend in multivariate)

30 High Expectations for Survival after BMT

31 Alternatives to Transplant Very poor organ function Kidney Liver Cardiac Pre existing infections Lung Blood Older Patient Age No donor ~45 (sibling donor) ~40 (unrelated donor) Alternatives Androgens Intermittent use of blood growth factor and transfusions other supportive care Experimental therapy (gene therapy or novel transplant protocol)

32 Cancer Risk Incidence 30% by age 45 years Observed to Expected Ratio Leukemia 785 Head/Neck 706 Esophagus 2362 Liver 386 Total 50 Rosenberg PS, Greene MH, Alter BP. Cancer incidence in persons with Fanconi s anemia. Blood 2003; 101:

33 Does Transplant Alter the Risk Conclusions Transplant is associated with high rate of solid tumors, particularly SCCs Association between GVHD [or its treatment] and SCCs - 33-fold higher risk with cgvhd Rosenberg, Blood 2005; 105: 67-73

34 How do we reduce cancer risk? Eliminate Bu and TBI Antibody based conditioning Higher stem cell doses PGD/IVF for HLA match and absence of FA Prevent GVHD T cell depletion of the graft Use of UCB PGD/IVF for HLA match and absence of FA Gene therapy Enhance immune reconstitution More HSCs Thymic progenitors Opportunistic infection Thymic shielding PGD/IVF for HLA match and absence of FA Gene therapy

35 Low risk of Grade II-IV AGvHD 1.0 with T Cell Depletion Cumulative Incidence Days Post-TX P = 0.47 Alternative donor (std. risk) Matched sibling

36 Low risk of Chronic GvHD with T 1.0 Cell Depletion Cumulative Incidence Months Post-TX P = 0.24 Matched sibling Alternative donor (std. risk)

37 Directions to Reduce Cancer Cumulative Incidence Risk in Fanconi Anemia Risk by Patient Age % (7-31%) by age 45 years Years of Age University of Minnesota

38 StemRegenin-1 Aryl Hydrocarbon Receptor (AhR) Pathway SR-1 directly binds and inhibits the AhR, blocking induction of CYP1B1 and impeding stem cell differentiation SR-1 mediated massive UCB stem cell expansion SR-1 L AhR XRE L AhR AhR Differentiation CYP1B1/AHRR Nucleus Cytosol Growth factor receptors CD34+ Cell Boitano et al. Science 2010;

39 Massive Expansion of Cord Blood Stem Cells 327-fold (n=37) C D C e l l N u m b e r s M Expansion a n u f a c t u r i n g o v e r v i e w 1 e 1 0 1, million e 9 1 e 8 1 e million F o l d E x p a n s i o n e B e f o r e A f t e r T o t a l c e l l s C D c e l l s C u l t u r e C u l t u r e

40 MGTA-456 after TBI 1320 cgy Faster Neutrophil Recovery, 100% engraftment MGTA-456 (single) 100% N=9/9 median 15 days Incidence p < Historical 83% (CI, 74-91) N=121 median 26.5 d (13-42) Days

41 Accelerated Immune Reconstitution after UCBT Myeloablative Conditioning M A C p r o to c o l x /µ l C D 4 C D 8 N K C D M o n th s p o s t T x Absolute CD4 200 at 2-3 months

42 Future of SR-1 Expanded HSPCs Manufacture of Thymic Progenitors UCB 1 CD34+ Selection Re- Cryopreserved CD34 - T Progenitor Dose Escalation 0.1 x 10 6 /kg 0.3 x 10 6 /kg 1.0 x 10 6 /kg Ex vivo culture HSC835 20% or maximum available Tprog ex vivo culture 3.0 x 10 6 /kg 10.0 x 10 6 /kg CY FLU CY FLU FLU REST TBI Repeat CD34+ Selection T cell tracking Days

43 Alcohol / Food Exposures and Cancer Risk

44 Use of assisted reproductive techniques IVF Preimplantation Genetic Diagnosis Savior Sibling IVF / PGD

45 PGD to prevent disease and save the life of an existing child PGD for mutation PGD for HLA Savior Sibling To eliminate risk of genetic disease To guarantee an HLA identical HSC donor

46 The Candidates 1995 Molly Henry

47 FANCC IVS4 A>T Mutation Predicting the Future

48 Verlinsky et al. JAMA 2004; 285,3130

49 Pregnancy

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51 Headlines The Creation of Adam

52 Back Lash

53 The path of the slippery slope Disease Prevention HLA Match Slippery Slope Gender Physical Features Longevity

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55 Parental Motivation Risks to the Donor

56 Future Gene Therapy Will it work?

57 Creating Somatic Mosaicism Chemotherapy? HSC NO Selective Growth Advantage Selective Growth Advantage Lessons of Nature

58 HSC Somatic Mosaicism 43 year old female - Healthy - MMC resistant - Clonal hematopoiesis - Double cross over event Natural Gene Therapy x x mitosis FANCA gene mutations x x Patient s Blood Control x x Selective growth advantage

59 Risk of MDS/AL in residual FA cells Lessons for FA Gene Therapy MMC resistant colonies 1) Maintenance of adequate (not normal) blood counts as an adult 2) Expected competitive growth advantage of revertant HSC not clear Betsy Hirsch, Ph.D. FISH with MLL probe exclusively found in colonies with FANCA mutations Gregory JJ et al PNAS 2001; 98:2532

60 Rare Disease Transforms the Practice of Medicine NMDP / Be the Match UCB Banking and Transplantation DNA Repair Genes FA Cures

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62 University of Minnesota BMT Program Pediatric BMT 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 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. Magenta Team Tony Boitano, Ph.D. Michael Cooke, Ph.D. Bastiano Sanna, Ph.D. Jason Gardner, Ph.D.