Robert A Brodsky MD Johns Hopkins Family Professor of Medicine and Oncology Director Division of Adult Hematology Glossary of terms BMT B one m arrow t ransplantation B lood or m arrow ID: 1007248
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1. Regenerative Medicine to Cure Sickle Cell AnemiaRobert A. Brodsky, MDJohns Hopkins Family Professor of Medicine and OncologyDirector: Division of Adult Hematology
2. Glossary of termsBMTBone marrow transplantationBlood or marrow transplantationStem cell transplantationHematopoietic cell transplantationPeripheral blood stem cell transplantationDonorSyngeneic – identical twinAutologous – self (blood or bone marrow)Allogeneic – another of same speciesMatched siblingAlternative DonorMatched unrelated donor (MUD)Non-matched sibling (haplo identical) Cord BloodHES or iPSC (not yet feasible)Synonyms
3. Glossary continued: Conditioning regimenMyeloablativeConditioning without BMT would lead to permanent aplasiaNon-myeloablative aka miniBMT, reduced intensityAutologous recovery would occur without BMT
4. Indications for Hematopoietic Stem Cell Transplants in the United States, 2009SUM-WW11_8.pptSlide 8Number of Transplants
5. Possibilities of BMTEradicate cancerLeukemiaLymphomaMDSReplace a defective organAplastic anemiaGenetic blood diseaseSickle cell anemiaThalassemiaReplace a defective immune system (autoimmunity)Lupus, MS, Crohn’s, RASolid organ transplantationNew/Future Uses
6. Obstacle to Success of BMTHematologic malignanciesToxicityGVHDDeathDonorsRelapseBiggest obstacle for hematologic malignanciesNon-malignant disease (e.g, Sickle cell)ToxicityGVHDDeathDonorsSAFETY and Donor availability
7. Reduced Intensity BMTLow-dose immunosuppressive conditioning to allow BMT to takeLower conditioning regimen toxicity Available to older (>70) and less fit patientsSubstantially cheaper than standard BMTOutpatient procedureNon-myeloablative or “mini” BMT
8. Genetics of HLA systemOne allele from each parentIf 1 sibling: 25% chance of inheriting same HLA allelle s (perfect match) If 2 siblings 44% chance of having perfect match.
9. Alternative Stem Cell SourcesMatched unrelated donor: available in 60% of Caucasians Rare for many ethnic groups - <10% of African-AmericansUmbilical cord – 2 antigen MM in 80%Delayed engraftment in adultsImmune dysfunction in adultsEmbryonic stem cellsPatient specific iPSCHaploidentical related – rapidly available to almost everyoneUnacceptably high rates of GVHD, historicallyMatched sibs available <30% ptsDon’t‘ engraft!
10. Alternative Donor AlloBMT (1997)The Holy Grail of BMT?Early LeukemiaIBMTRSzydlo et al JCO 1997Early Leukemia
11. High Dose Cyclophosphamide to Mitigate Alloimmunity Transport forms:aldophosphamide4-hydroxyCy Metabolized by:ALDHHSCHigh levels ALDHresistantLymphocytesLow levels ALDHsensitiveEmadi, Jones and Brodsky. Nat Rev Clin Oncol 2009
12. Post Transplant High Dose CyMitigates GVHD Allows for greater use of alternative donors (haplo BMT)Average person in US has 4.5 HLA haplo-identical donorsHelpful for malignant diseases but may revolutionize the treatment of genetic and autoimmune disease
13. HypothesisNon-myeloablative conditioning with post transplant HiCY will expand the number of SCD patients eligible for allogeneic BMT by allowing the safe and effective use of related HLA-haploidentical donors
14. Sickle Cell Anemia First Genetic DiseaseHydroxyurea only FDA approved drug
15. Genetics of Sickle Cell Disease
16. Epidemiology1:400 births in African Americans1:36,000 births in Hispanics1:123,000 births in Whites~ 100,000 in US with SCDMedian survival 42 yrs in malesMedian survival 48 yrs in femalesSCD kills an estimated half-million people worldwide annually.
17. Annual cost of medical care in the US for people who suffer from sickle cell disease exceeds $1.1 billionAverage cost per patient: $2000 / month10k/yr for children35K/yr for adults45 yo with SCD will cost $1 million lifetime"When one considers the additional contributions of sickle cell disease associated with reduced quality of life, uncompensated care, lost productivity, and premature mortality, the full burden of sickle cell disease is likely to be quite higher." Kauf et al, Am J Hematol. 2009
18. BMT for Sickle Cell Disease1st 1984 in patient with AMLKnown cure, but many obstaclesNeed for HLA-matched sibling <8% of patients have a suitable donorCord blood results have been disappointingToxicity of conditioning regimenNon-myeloablative preps have had high rates of graft failureHigh rate of graft failure
19. Reduced intensity haploidentical BMT with post-transplant Cyclophosphamide (CY)ATG Day -9 to -7Bolanos-Meade et al, Blood 2012~Alloreactive T cells maximally stimulated at days 3-4 postBMTNon-alloreactive T cells quiescentMemory T cells (like HSCs) relatively resistant to Cy via high expression of ALDH
20. Expanding the Availability of BMT for SCD19 patients screened (17 adult; 2 pediatric)17 transplanted (90%)3 matched sibling donors (all 3 engrafted) 14 haplo donors (8 engrafted)11/19 (58%) of screened patients cured11/17 (65%) of transplanted patients curedNo mortality No GVDH that required treatment
21. 27 yo female with SCD and LupusT = 03 mos6mos RecentC357156141107C414373721Anti-DNA+---Hbg6.510.09.813.5Abs Retic448K122K49K37KLDH355186180HB S86.126.236.837.7
22. ConclusionsAllogeneic BMT is the only cure for SCD HiCY post BMT safely expands the donor pool by allowing for the use of haploidentical donorsThe majority of patients with SCD are potentially eligible for therapy with curative intentGraft failure remains an obstacle when using haploidentical donors
23. Engraftment with G-CSF-primed DonorsPt/Age/sexIndication for bmtDonorDate of BMTLast Hgb% donor red cells% donor myeloid cells% donor T cells20/fOsteonecrosisAcute chestHaplomother10/20119.7*N/A0021/fStrokeAcute chestHaplosister11/201113.410010010015/fStrokeMoyamoyaHaplomother11/201113.510010010026/fAcute chestIron overloadHaplohalf-brother7/201212.310082<539/mVOCalloimmunizationHaplofather9/201210.0100954726/mStrokeHaploMother9/20129.51009095* Hgb reflects transfusion of RBCs within last 90 days
24. Future Directions Genetic disease of stem cellsSickle cell disease, ThalassemiaGoal to increase engraftment to >75%Autoimmune diseaseLupus, Crohn’s disease etc.Solid organ transplantation
25. Take homeMorbidity and mortality following Allo BMT has decreased substantiallyBetter supportive careReduced intensity prep regimensPost transplant CyAlternative donor transplants are a realityVirtually everyone has a donorBMT for genetic disease, autoimmunity and solid organ transplantation is the next frontier
26. AcknowledgmentsGeorge SantosAlbert OwensLyle SensenbrennerRick JonesEphraim FuchsLeo LuznikSophie LanzkronChris GamperJavier Bolanos-MeadeSue LeffellLaboratoryClinicJHU NursingJHU HousestaffPatients/Families