Advancements in Regenerative Medicine for Sickle Cell Anemia

 
Regenerative Medicine to Cure Sickle
Cell Anemia
 
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 
t
ransplantation
Stem cell transplantation
Hematopoietic cell transplantation
Peripheral blood stem cell transplantation
 
 
Donor
Syngeneic – identical twin
Autologous – self (blood or bone marrow)
Allogeneic – another of same species
Matched sibling
Alternative Donor
Matched unrelated donor (MUD)
Non-matched sibling (haplo identical)
Cord Blood
HES or iPSC (not yet feasible)
 
Glossary continued: Conditioning regimen
 
Myeloablative
Conditioning without BMT would lead to
permanent aplasia
 
Non-myeloablative
aka miniBMT, reduced intensity
Autologous recovery would occur without BMT
 
Indications for Hematopoietic Stem Cell
Indications for Hematopoietic Stem Cell
Transplants in the United States, 2009
Transplants in the United States, 2009
 
SUM-WW11_8.ppt
 
Slide 8
 
Number of Transplants
Possibilities of BMT
 
Eradicate cancer
Leukemia
Lymphoma
MDS
 
Replace a defective
organ
Aplastic anemia
 
Genetic blood disease
Sickle cell anemia
Thalassemia
 
Replace a defective immune
system (autoimmunity)
Lupus, MS, Crohn’s, RA
 
Solid organ transplantation
Obstacle to Success of BMT
Hematologic
malignancies
Toxicity
GVHD
Death
Donors
Relapse
Biggest obstacle for
hematologic
malignancies
Non-malignant disease
(e.g, Sickle cell)
Toxicity
GVHD
Death
Donors
 
SAFETY and Donor availability
 
Reduced Intensity BMT
 
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Lower conditioning regimen toxicity
Available to older (>70) and less fit patients
Substantially cheaper than standard BMT
Outpatient procedure
 
 
 
 
 
Non-myeloablative or “mini” BMT
 
Genetics of HLA system
 
One allele from each parent
 
If 1 sibling: 25% chance of inheriting same HLA
allelle s (perfect match)
 
If 2 siblings 44% chance of having perfect
match.
Alternative Stem Cell Sources
 
Matched unrelated donor: available in 
 
60% of Caucasians
Rare for many ethnic groups - <10% of African-Americans
 
 
Umbilical cord – 2 antigen MM in 80%
Delayed engraftment in adults
Immune 
dysfunction in adults
 
Embryonic stem cells
 
Patient specific iPSC
 
 
Haploidentical related – rapidly available to almost everyone
Unacceptably high rates of GVHD, historically
Matched sibs available <30% pts
 
Alternative Donor AlloBMT (1997)
 
The Holy Grail of BMT?
 
Early Leukemia
 
IBMTR
Szydlo 
et al JCO
 1997
 
Early Leukemia
High Dose Cyclophosphamide to Mitigate
Alloimmunity
 
Transport forms:
aldophosphamide
4-hydroxyCy
 
Metabolized by:
ALDH
 
HSC
High levels ALDH
resistant
 
Lymphocytes
Low levels ALDH
sensitive
 
Emadi, Jones and Brodsky. Nat Rev Clin Oncol 2009
 
Post Transplant High Dose Cy
 
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Hypothesis
 
Non-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
 
Sickle Cell Anemia
 
 
 
First Genetic Disease
 
Hydroxyurea only FDA approved drug
 
Genetics of Sickle Cell Disease
 
Epidemiology
 
1:400 births in African Americans
1:36,000 births in Hispanics
1:123,000 births in Whites
 
~ 100,000 in US with SCD
Median survival 42 yrs in males
Median survival 48 yrs in females
 
SCD kills an estimated half-million people worldwide
annually.
 
Annual cost of medical care in the US for
people who suffer from sickle cell disease
exceeds $1.1 billion
 
Average cost per patient: $2000 / month
10k/yr for children
35K/yr for adults
45 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
 
BMT for Sickle Cell Disease
 
1
st
 1984 in patient with AML
 
Known cure, but many obstacles
Need for HLA-matched sibling
<8% of patients have a suitable donor
Cord blood results have been disappointing
Toxicity of conditioning regimen
Non-myeloablative preps have had high rates of graft failure
High rate of graft failure
Reduced intensity haploidentical BMT 
with post-transplant Cyclophosphamide (CY)
 
ATG Day -9 to -7
 
Alloreactive T cells maximally stimulated at days 3-4 postBMT
Non-alloreactive T cells quiescent
Memory T cells (like HSCs) relatively resistant to Cy via high
expression of ALDH
 
Expanding the Availability of BMT for SCD
 
19 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 cured
11/17 (65%) of transplanted patients cured
 
 
No mortality
 
No GVDH that required treatment
27 yo female with SCD and Lupus
 
Conclusions
 
Allogeneic BMT is the only cure for SCD
 
HiCY post BMT safely expands the donor pool by
allowing for the use of haploidentical donors
 
The majority of patients with SCD are potentially
eligible for therapy with curative intent
 
Graft failure remains an obstacle when using
haploidentical donors
 
Engraftment with G-CSF-primed Donors
 
*
 
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Future Directions
 
Genetic disease of stem cells
Sickle cell disease, Thalassemia
Goal to increase engraftment to >75%
 
Autoimmune disease
Lupus, Crohn’s disease etc.
Solid organ transplantation
Take home
 
Morbidity and mortality following Allo BMT has
decreased substantially
Better supportive care
Reduced intensity prep regimens
Post transplant Cy
 
Alternative donor transplants are a reality
Virtually everyone has a donor
 
BMT for genetic disease, autoimmunity and
solid organ transplantation is the next frontier
 
 
Acknowledgments
George Santos
Albert Owens
Lyle Sensenbrenner
Rick Jones
Ephraim Fuchs
Leo Luznik
Sophie Lanzkron
Chris Gamper
Javier Bolanos-Meade
Sue Leffell
 
Laboratory
Clinic
 
JHU Nursing
JHU Housestaff
Patients/Families
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Regenerative medicine holds promise for treating sickle cell anemia through techniques like stem cell transplantation. This approach targets genetic blood diseases, offering potential cures beyond traditional uses like eradicating cancer. Despite obstacles like toxicity and donor availability, innovative methods like reduced intensity BMT show potential benefits, including lower toxicity and outpatient procedures.

  • Regenerative Medicine
  • Sickle Cell Anemia
  • Stem Cell Transplantation
  • Genetic Blood Diseases
  • Advancements

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  1. Regenerative Medicine to Cure Sickle Cell Anemia Robert A. Brodsky, MD Johns Hopkins Family Professor of Medicine and Oncology Director: Division of Adult Hematology

  2. Glossary of terms BMT Bone marrow transplantation Blood or marrow transplantation Stem cell transplantation Hematopoietic cell transplantation Peripheral blood stem cell transplantation Synonyms Donor Syngeneic identical twin Autologous self (blood or bone marrow) Allogeneic another of same species Matched sibling Alternative Donor Matched unrelated donor (MUD) Non-matched sibling (haplo identical) Cord Blood HES or iPSC (not yet feasible)

  3. Glossary continued: Conditioning regimen Myeloablative Conditioning without BMT would lead to permanent aplasia Non-myeloablative aka miniBMT, reduced intensity Autologous recovery would occur without BMT

  4. Indications for Hematopoietic Stem Cell Transplants in the United States, 2009 5,500 Allogeneic (Total N=7,012) Autologous (Total N=9,778) 5,000 4,500 4,000 Number of Transplants 3,500 3,000 2,500 2,000 1,500 1,000 500 0 Multiple Myeloma NHL AML HD ALL MDS/MPD Aplastic CML Other Leuk Non- Malig Disease Other Cancer Anemia Slide 8 SUM-WW11_8.ppt

  5. Possibilities of BMT Traditional Uses New/Future Uses Eradicate cancer Leukemia Lymphoma MDS Genetic blood disease Sickle cell anemia Thalassemia Replace a defective immune system (autoimmunity) Lupus, MS, Crohn s, RA Replace a defective organ Aplastic anemia Solid organ transplantation

  6. Obstacle to Success of BMT Hematologic malignancies Toxicity GVHD Death Donors Relapse Biggest obstacle for hematologic malignancies Non-malignant disease (e.g, Sickle cell) Toxicity GVHD Death Donors SAFETY and Donor availability

  7. Reduced Intensity BMT Non-myeloablative or mini BMT Low-dose immunosuppressive conditioning to allow BMT to take Lower conditioning regimen toxicity Available to older (>70) and less fit patients Substantially cheaper than standard BMT Outpatient procedure

  8. Genetics of HLA system One allele from each parent If 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 Sources Matched sibs available <30% pts Matched unrelated donor: available in 60% of Caucasians Rare for many ethnic groups - <10% of African-Americans Umbilical cord 2 antigen MM in 80% Delayed engraftment in adults Immune dysfunction in adults Embryonic stem cells Patient specific iPSC Don t engraft! Haploidentical related rapidly available to almost everyone Unacceptably high rates of GVHD, historically

  10. Alternative Donor AlloBMT (1997) The Holy Grail of BMT? Early Leukemia Early Leukemia IBMTR Szydlo et al JCO 1997

  11. High Dose Cyclophosphamide to Mitigate Alloimmunity Transport forms: aldophosphamide 4-hydroxyCy Metabolized by: ALDH HSC High levels ALDH resistant Lymphocytes Low levels ALDH sensitive Emadi, Jones and Brodsky. Nat Rev Clin Oncol 2009

  12. Post Transplant High Dose Cy Mitigates GVHD Allows for greater use of alternative donors (haplo BMT) Average person in US has 4.5 HLA haplo- identical donors Helpful for malignant diseases but may revolutionize the treatment of genetic and autoimmune disease

  13. Hypothesis Non-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 Disease Hydroxyurea only FDA approved drug

  15. Genetics of Sickle Cell Disease

  16. Epidemiology 1:400 births in African Americans 1:36,000 births in Hispanics 1:123,000 births in Whites ~ 100,000 in US with SCD Median survival 42 yrs in males Median survival 48 yrs in females SCD 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 billion Average cost per patient: $2000 / month 10k/yr for children 35K/yr for adults 45 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 Disease 1st 1984 in patient with AML Known cure, but many obstacles Need for HLA-matched sibling <8% of patients have a suitable donor Cord blood results have been disappointing Toxicity of conditioning regimen Non-myeloablative preps have had high rates of graft failure High rate of graft failure

  19. Reduced intensity haploidentical BMT with post-transplant Cyclophosphamide (CY) ATG Day -9 to -7 Alloreactive T cells maximally stimulated at days 3-4 postBMT Non-alloreactive T cells quiescent Memory T cells (like HSCs) relatively resistant to Cy via high expression of ALDH Bolanos-Meade et al, Blood 2012 ~

  20. Expanding the Availability of BMT for SCD 19 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 cured 11/17 (65%) of transplanted patients cured No mortality No GVDH that required treatment

  21. 27 yo female with SCD and Lupus T = 0 3 mos 6mos Recent C3 57 156 141 107 C4 14 37 37 21 Anti-DNA + - - - Hbg 6.5 10.0 9.8 13.5 Abs Retic 448K 122K 49K 37K LDH 355 186 180 HB S 86.1 26.2 36.8 37.7

  22. Conclusions Allogeneic BMT is the only cure for SCD HiCY post BMT safely expands the donor pool by allowing for the use of haploidentical donors The majority of patients with SCD are potentially eligible for therapy with curative intent Graft failure remains an obstacle when using haploidentical donors

  23. Engraftment with G-CSF-primed Donors Pt/Age/sex Indication for bmt Donor Date of BMT Last Hgb % donor red cells % donor myeloid cells % donor T cells 20/f Osteonecrosis Acute chest Haplo mother 10/2011 9.7* N/A 0 0 21/f Stroke Acute chest Haplo sister 11/2011 13.4 100 100 100 15/f Stroke Moyamoya Haplo mother 11/2011 13.5 100 100 100 26/f Acute chest Iron overload Haplo half-brother 7/2012 12.3 100 82 <5 39/m VOC alloimmunization Haplo father 9/2012 10.0 100 95 47 26/m Stroke Haplo Mother 9/2012 9.5 100 90 95 * Hgb reflects transfusion of RBCs within last 90 days

  24. Future Directions Genetic disease of stem cells Sickle cell disease, Thalassemia Goal to increase engraftment to >75% Autoimmune disease Lupus, Crohn s disease etc. Solid organ transplantation

  25. Take home Morbidity and mortality following Allo BMT has decreased substantially Better supportive care Reduced intensity prep regimens Post transplant Cy Alternative donor transplants are a reality Virtually everyone has a donor BMT for genetic disease, autoimmunity and solid organ transplantation is the next frontier

  26. Acknowledgments Laboratory JHU Nursing JHU Housestaff Patients/Families George Santos Albert Owens Lyle Sensenbrenner Rick Jones Ephraim Fuchs Leo Luznik Sophie Lanzkron Chris Gamper Javier Bolanos-Meade Sue Leffell Clinic

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