Are We There Yet? Gene Therapy and BMT as Curative Therapies in Sickle Cell. Ann Haight, MD 9 Sept 2017

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1 Are We There Yet? Gene Therapy and BMT as Curative Therapies in Sickle Cell Ann Haight, MD 9 Sept 2017

2 Spoiler alert Yes (we have a cure) And No Work to do! 2

3 Sickle Cell Treatment Options Supportive Care Newborn Screen PCN Immunizations Education Disease Interventions Hydroxyurea Transfusion therapy Iron chelation therapy Curative Bone Marrow Transplantation (BMT) Gene Therapy 3

4 Bone Marrow Transplantation Curative therapy for sickle cell disease Center for International Blood & Marrow Transplant Research (CIBMTR): Over 1000 sickle cell patients have received BMT to-date Most are pediatric Vast majority in recent years Survival Statistics for Matched Related Donor transplants: 93+% overall survival (97% at CHOA) 85+% event free survival (97% at CHOA) 4

5 Dramatic increase in the numbers SCD patients undergoing HCT 5

6 CHOA/Emory pediatric BMT experience 78 pediatric SCD patients transplanted to-date Matched sibling donor BMT considered a standard of care for moderate/severe SCD Matched Sibling Donor 70 patients 68/70 (97%)overall survival 1 early death (agvhd), 1 later death (infx) Alternative Donor 8 patients: One 7/8-matched sibling 3 unrelated cord blood; 4 matched unrelated Survival: 1 engraftment failure (cord) alive/reconstituted 3 deaths 2 severe agvhd 1 very late death Aflac 4 cured/alive Cancer and Blood (1 of Disorders whom has Center severe Emory cgvhd) University 6

7 Bone Marrow Transplantation - Barriers TOXICITY Short Term: immunosuppression, infection, graft-vs-host, acute organ dysfunction Long Term: chronic graft-vs-host, chemotherapy late effects, infertility DONOR AVAILABILITY Matched Related Donor Least morbidity; Majority lack a related donor Alternative Donors Matched Unrelated; Cord Blood; Haplo-identical 7

8 Transplant is not a drive-thru! Cell Infusion -10 Preparative Regimen Engraftment Recovery Phase TIME (Days) C U R E

9 Bone Marrow Transplantation Graft options HLA typing Source Bone marrow Gold standard Most commonly used Cord blood Privately banked Public cord banks Peripheral blood stem cells Faster engraftment More chronic GVHD

10 Eligibility for BMT Traditional Criteria Suitable Donor Patient Age Severe Genotype Severe Phenotype HLA-identical sibling donor Under 16 years old HbSS HbSβ 0 thalassemia Stroke risk Multiple ACS Frequent VOC Pain Chronic organ damage: - Nephropathy - Retinopathy - Osteonecrosis Alloimmunization in chronic transfusions 10

11 Eligibility for BMT New Considerations Non-severe disease Offer BMT to young children who have a young matched sibling, irrespective of disease severity/phenotype Outcomes predictably good, with low rates of GVHD in the young donor/recipient Emphasis on intensive family education and psychosocial assessment Severe disease Expand the donor pool BeTheMatch donors Haploidentical transplant protocols Atlanta s Transform now open Prevent and control GVHD for those at higher risk Clinical trials STAR-Abatacept trial open/enrolling New FDA approval of cgvhd drug 11

12 Considering a BMT, what s next step? Talk to hematologist Get HLA typing done on patient and full siblings Get more information Atlanta Sickle Education Day STELLAR symposium (Oct 28 th, 2017) Websites CHOA BMT InfoNet.org Be The Match.org Clinicaltrials.gov CureSickleNow.org (STAR) Sickleoptions.org Seek a formal BMT consult visit Connect with a family

13 Gene therapy for sickle cell Early clinical trials (current Phase I) Autologous transplant of patient s bone marrow stem cells that have undergone genetic transfer of anti-sickling gene a modified β-globin gene that inhibits HbS polymerization Lentiviral vector transmission Eliminates problems of donor availability or graft-vs-host complications of allogeneic HSCT DOES have chemotherapy Currently available at CHOA for certain patients 18yo+ Severe disease only 13

14 Gene Brief Therapy: Overview An of emerging Gene Therapy Curative for Therapy SCD for Sickle Cell Disease Kanter, J. FSCDR Annual meeting 2015

15 Fertility and genetic considerations Chemotherapy (alkylators) causes infertility risk Not absolute, and may change over time Several children born to our sickle BMT patients Infertility may be significant concern for families Understanding ongoing genetic transmission risk is key SS BMT patients are cured but WILL still pass on the S gene Role for age appropriate and repeated discussions Fertility counseling and preservation options Aflac fertility preservation team consult Sperm banking Oocyte harvest 15

16 Roles for the primary care pediatrician Supporting families in the decision making process Advocating for the matched sibling donor Resuming primary pediatric care Encouraging late-effects follow up Post-BMT revaccinations 16

17 Questions?