Bone marrow transplantation: The next frontier

1. Bone marrow transplantation: The next frontier Robert A. Brodsky, MD The Johns Hopkins Family Professor of Medicine and Oncology Director, Hematology

2. Disclosures • Dr. Brodsky serves as a Scientific Advisory Board member to Alexion Pharmaceuticals. • Consultant: VeroPharma • Consultant: Alnylan

3. New/Future Uses Possibilities of BMT • Eradicate cancer • AML, ALL, MDS, CML, CLL, Lymphoma etc. • Replace a defective organ • Acquired SAA • Inherited BMF • Gene therapy • Sickle cell anemia • Thalassemia • CGD • Replace a defective immune system (autoimmunity) • Lupus, MS, Crohns, SSc, RA • Solid organ transplantation

4. Indications for Hematopoietic Stem Cell Transplants in the United States, 2009 Number of Transplants Slide 8 SUM-WW11_8.ppt

5. Causes of Death after Transplants performed in2008-2009 HLA-identical Sibling New Malignancy (1%) Primary Disease (47%) GVHD (14%) Unrelated Donor Infection (12%) New Malignancy (1%) Primary Disease (33%) Organ Failure (4%) Other (21%) GVHD (15%) Autologous Primary Disease (73%) New Malignancy (1%) Infection (8%) Infection (16%) Other (29%) OrganFailure (6%) Organ Failure (2%) Other (16%) Slide 18 SUM-WW11_17.ppt

6. “BMT See-Saw” Relapse GVHD Relapse

7. Obstacle to Success of BMT • Hematologic malignancies • Relapse • Death • GVHD • Suitable donors • Engraftment • Morbidity • Cost • Non-malignant disease (e.g, SCD, PNH, SAA) • Death • GVHD • Suitable donors • Engraftment • Morbidity • Cost SAFETY and Donor availability

8. 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

9. Alternative Donor AlloBMT Matched sibs available <30% pts • MUD 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 • Haploidentical related – rapidly available to almost everyone • Unacceptably high rates of GVHD, historically

10. Alternative Donor AlloBMT Pediatric BMT (2010) TRM Grade 3-4 Acute GVHD mMRD mMRD Cumulative incidence MUD MUD MSD MSD CIBMTR Shaw et al Blood 2010

11. High Dose Cy to Mitigate Alloimmunity • Biggest single advance in the field of BMT in the last 25 years?

12. Cyclophosphamide Pharmacology • Transport forms: • aldophosphamide • 4-hydroxyCy • Metabolized by: • ALDH • HSC • High levels ALDH • resistant • Lymphocytes • Low levels ALDH • sensitive Emadi, Jones and Brodsky. Nat Rev ClinOncol 2009

13. NonmyeloablativeHaploBMT High-dose Cy GVHD prophylaxis • 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 Luznik et al BBMT 2008

14. Haplovs Cord Transplants (Hememalignanies) Simultaneous phase II BMT CTN trials Brunsteinet al Blood 2011

15. Haplo and Cord Transplants Simultaneous phase II BMT CTN trials Acute GVHD Brunsteinet al Blood 2011

16. Haplo and Cord Transplants Simultaneous phase II BMT CTN trials Brunsteinet al Blood 2011

17. 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 • Great for malignant diseases but may revolutionize the treatment of genetic and autoimmune disease

18. 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 Clinical Research Forum: Top 10 most important clinical research papers in 2013

19. Why is this such a major advance? • HiCY post BMT safely expands the donor pool by allowing for the use of haploidentical (half-matched donors) • The majority of patients with SCD are potentially eligible for therapy with curative intent • Limitations: Only 8 of the 14 patients who received the half-matched bone marrow kept the graft and were cured of SCD

20. G-CSF Stimulation of Donors Improves Harvest Cell Count

21. G-CSF Stimulated Donors Increases Engraftment After MiniHaplo in SCD • 26 consecutive allotransplants in SCD • Before G-CSF in 8/14 (57%) • Since G-CSF 10/12 (83%) • All but one half-matched (Haplos) • No mortality • 1 patient with mild GVHD

22. HaploBMT for Lupus? • Fever, failure to thrive 1st year of life – hgb SS disease • 2002 lupus diagnosis • Skin rash, alopecia, nephritis, polyarthritis, • Unresponsive to drug therapy • 2005 renal vein thrombosis • 2010 Sickle cell crises more severe and frequent (once a month) • No matched sibling donor; brother 3/6 half match (HLA-haploidentical).

23. Clinical Course

24. Take home • Morbidity and mortality following Allo BMT has decreased substantially • Better supportive care • More accurate typing • Better GVHD prophylaxis • Reduced intensity prep regimens • Post transplant Cy • Alternative donor transplants are a reality • Virtually everyone has a donor • For hematologic malignancies, relapse remains the leading cause of death after BMT • BMT for genetic diseases, autoimmunity and solid organ transplantation is the next frontier