Hematopoietic Stem Cell Transplantation for Fanconi Anemia

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1 Hematopoietic Stem Cell Transplantation for Fanconi Anemia John E. Wagner, M.D. Blood and Marrow Transplant Program University of Minnesota Cell Therapy for Pediatric Diseases NHLBI PACT Workshop September 2011 Classic Manifestations of FA Short stature Renal agenesis Radial ray defects Marrow failure

2 >14 genes identified Defect in DNA repair pathway Defined natural history (phenotype/genotype correlations but ethnic and racial variations) Fanconi Anemia Broad impact (model for 100 understanding DNArepair repair, 80 cancer biology, stem cell 60 survival, organogenesis) CFC relative to con ntrol Selective growth advantage of 20 normal HSC Revertant FA BM 40 FA BM Normal BM MMC Fanconi Anemia Predisposition to Marrow Failure and Cancer Median age of diagnosis is 7 years Most early deaths are due to BM failure or leukemia Most late deaths are due to solid tumor Blood 2003; 101:1249

3 State of BMT for FA in 1995 PROBABILITY OF SURVIVAL AFTER ALLOGENEIC TRANSPLANTS FOR FANCONI ANEMIA BY IBMTR DONOR /ABMTR TYPE Newsletter AND AGE, 1 Feb PR ROBABILITY, % HLA-identical sibling, 10y (N = 109) HLA-identical sibling, 10y (N = 100) Unrelated, 10y (N = 36) P = Unrelated, 10y (N = 58) YEARS Reasons for Poor Outcomes in Patients with an Unrelated Donor Sibling Donor HLA matched Earlier treatment Cy 20 TAI 500 cgy Unrelated Donor HLA mismatched Late treatment Cy 40 TBI >450 cgy Good Outcome Poor Outcome

4 Setting the Agenda Fanconi Anemia Research Fund Identify potential solutions Have an HLA matched donor Fund the work Identification of Genes Gene Therapy Trials BMT Trials Development of Unrelated Donor Registry PGD/IVF Savior Sibling Sb Observations Deliberate Conception Pregnancies (n=77) Normal (n=63) Affected (n=14) HLA matched (n=12) 19.04% Elective abortion (n=3) 7.9% Elective abortion (n=10) 71.4% Auerbach AD, Blood Cells 1994

5 Umbilical Cord Blood Transplant New Source of HSC UCB collected in North Carolina Tested at Rockefeller, Indiana University and Baylor Shipped to Paris Broxmeyer et al. Observations Deliberate Conception Pregnancies (n=77) Normal (n=63) Affected (n=14) HLA matched (n=12) 19.04% Elective abortion (n=3) 7.9% Elective abortion (n=10) 71.4% Auerbach AD, Blood Cells 1994

6 zona pellucida PGD to prevent disease and save the life of an existing child PGD for mutation PGD for HLA To eliminate risk of genetic disease blastomeres To create an HLA identical stem cell donor Embryo 4

7 Cum mulative proportio on Fanconi Anemia Survival after HLA matched UCBT n=14 40% success rate Maternal age factor October Months after HSCT Cum mulative proportio on Fanconi Anemia/Aplasia Transplant Outcomes after HLA matched BMT/UCBT BM CD34 selected (n=16) UCB (n=12)* No graft failure No GVHD No TRM Conditioning n=28 FLU 35 mg/m2 x 4 CY 5 mg/kg g x 4 CsA for 60 days Months after HSCT

8 Unrelated Donor HSCT for FA Tackling Problems Poor engraftment Intolerance to GVHD and/or its treatment High risk of infection GVHD low (18%) Graft failure high (35%) Survival better (23%) Cy 10 mg/kg/day x 4 days TBI 450 cgy CsA T cell depleted BM Unrelated Donor HSCT for FA Tackling Problems Series of patient trials Add TCD Add fludarabine Add thymic shielding TBI dose de escalation GVHD solved GF solved Reduced OI? Too early

9 Radiation Therapy Thymic Shielding Total (Ant+Post) Dose(% %) Left Lung Left Lung Right Lung Posterior beam Anterior beam Distance Mean dose Maximum dose Thymus 15% (45 cgy) 17% (51 cgy)

10 Thymic Shielding Reduces Risk of Infections Total # Infections per Patient # Bacterial Infections per Patient # Viral Infections per Patient # Fungal Infections per Patient TBI 450 including Thymus TBI 450 with Thymic Shielding TBI 300 with Thymic Shielding P value P < 0.01 P < 0.01 P < 0.01 P < 0.01 Small Patient Trials Impact on Survival Cum mulative Proportion I 1.0 I 2006 FLU/CY/ATG/ TBI 300/150 TS 89% II II I I I I II FLU/CY/ATG/450TBI TS 75% I I I I I II I I I I I FLU/CY/TBI/ATG, TCD 67% CY/TBI, TCD 23% Years

11 TBI 450 TBI 300 TBI 150 Unrelated Donor HSCT For FA Thymic Shielding D/C CY10 CY10 CY10 CY10 FLU 35 FLU 35 FLU 35 FLU 35 ATG ATG ATG ATG ATG HCT TCD BM UCB MP (Day 5 to 15) CSA (Day 180) G CSF (ANC 2500) Good Engraftment Despite Thymic Shielding and Reduced Dose TBI Cumu ulative Proportion /150 TS 95% I 450 no TS 95% 450 TS 92% P=0.74 Median 11 days (9 30) I Days

12 Low Risk of Acute GVHD with TCD Low Risk Chronic GVHD 1.0 Cu umulative Incidence e P= /150 TS 0% 450 no TS 19% 450 TS 8% Months after HCT

13 University of Minnesota Unrelated HSCT for FA 1.0 I I I I Patients 10 yrs old or less 100% (n=10) Cu umulative Proportio on I I I I I I I II I I I I I All patients including adults 83% (55 94%) (n=28) Years TBI 300 Thymic Shield ding Unrelated Donor HSCT For FA CY10 CY10 CY10 CY10 FLU 35 FLU 35 FLU 35 FLU 35 ATG ATG ATG ATG ATG HCT TCD BM UCB MP Quality of Life Risk of avascular necrosis Risk of infection Need for insulin MMF days 0 to 35 (Day 55 to 15) CSA (Day 180) G CSF (ANC 2500)

14 Lessons Learned General Embedresearch and clinical care, clearly demarcating the two Educate the FDA reviewers about the disease and its severity Enlist outside consultants to insure objectivity about patient eligibility and responses to therapy Develop a roadmap, making one change at a time Lessons Learned Disease specific Utilize patient t advocacy groups to help direct questions next questions TCD even for those with HLA genotypic identical donors Embryo selection to generate seed funding

15 plants Number of Transp Cumulative Fanconi Anemia Pathway to Cure Minnesota FA Research 201 Program URD RD transplants (6/2010) Cumulative High dose therapy Dose reduced therapy st Umbilical cord blood transplant 96 1 st T cell depletion for URD BMT st successful PGD/IVF TBI dose escalation study 1 st use of fludarabine Gene therapy?