Hematopoietic Stem Cell Transplant (HCT) for Nonmalignant Disorders Evan Shereck, M.D.

1. Hematopoietic Stem Cell Transplant (HCT) for Nonmalignant Disorders Evan Shereck, M.D. September 13, 2013

2. Objectives • Overview of nonmalignant disorders - Immunodeficiencies - Genetic/metabolic disorders - Inherited blood disorders - Bone marrow failure syndromes • Review outcome of HCT for selected nonmalignant diseases • Discuss donor issues specific to nonmalignant diseases

3. Indications for Pediatric BMT

4. Indications for HCT for Patients < 20 years 800 Allogeneic (Total N=1,496) 700 Autologous (Total N=880) 600 500 Number of Transplants Number of Transplants 400 36% 300 200 100 0 Other ALL AML Aplastic HD NHL MDS/MPD CML Other Non- Cancer Anemia Leuk Malig Disease

5. The Cells Produced in Bone Marrow

6. Immune System 101

7. Primary Immunodeficiencies • Genetically heterogeneous group of diseases affecting distinct components of innate and adaptive immunity - Lymphocytes (T, B cells) - Natural killer cells - Neutrophils - Dendritic cells - Complement proteins • More than 120 gene defects have been described

8. Primary Immunodeficiencies Treated with HCT

9. Natural History of Inherited Immunodeficiencies • Spectrum of disease depends on genetic defect

10. Known Severe Combined Immunodeficiencies

11. Outcomes of HCT for SCID MRD (matched related donor), Haplo (haplocompatible family donor), MUD (matched unrelated donor) Percentage indicates overall survival , Number in parentesis = number of patients

12. Effect of Age on Transplant Percent Surviving Day of Life at Transplant Rebecca H. Buckley, J. All & Clin Immunol, 2012

13. SCID Newborn Screen

14. Unique Features for HCT for SCID • Bad disease  need HCT ASAP, any suitable donor • Conditioning not needed for “complete” SCID • Most patients needs some form of conditioning - Maternal T-cell engraftment at birth - Dysfunctional/over-reactive T-cells • High rates of toxicity, TRM and GVHD observed • Goal is to condition with minimal amount of conditioning necessary to achieve engraftment • Full donor chimerism usually not necessary • Newborn screening in some states

15. Inherited Metabolic Diseases • Genetic defects in enzymes  accumulation of metabolic products in body organs  progressive dysfunction  death • Multiple diseases, some amenable to HCT some not Rule of thumb: If replacing leukocytes can generate the missing enzyme, then HCT may be effective • Time is of essence Ultimate outcome and QOL not improved if end-organ symptoms are present

16. Lysosomes

17. Metabolic Disorders & Transplantation Standard of care Under Investigation Hunter I-cell Recessive Osteopetrosis Niemann-Pick Gaucher Farber Tay-Sachs • MPS IH (Hurler) • Metachromatic leukodystrophy (MLD) • Globoid Cell leukodystrophy (Krabbe) • -mannosidosis • acid lipase deficiency (Wolman disease) • Cerebral ALD

18. Strategies to Replace Enzymes Enzyme replacement therapy (“ERT”) • Required for the life of the patient • Does not penetrate into the brain Gene Therapy • Correction of patient’s own cells • Over-produce missing enzyme in other cells Cellular therapy with “normal” cells • HCT: how does this help the brain?

21. The Challenge of Fixing the CNS: Microglia • Cells of the immune system within the brain • About 15% of cells in the brain are microglia • Derived from hematopoietic precursors • Likely takes months for these cells to make their way into the brain • Timing is of essence

22. Hurler Syndrome (MPS IH) Signs and symptoms Macrosomia Developmental delay Chronic rhinitis/otitis Corneal clouding Obstructive airway disease Hearing loss Umbilical/inguinal hernia Enlarged tongue Cardiovascular disease Skeletal deformities Hepatosplenomegaly Carpal tunnel syndrome Joint stiffness Neufeld EF, Muenzer J. In: Scriver C, Beaudet A, Sly W, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. New York, NY: McGraw-Hill; 2001:3421-3452.

23. HCT for Hurler syndrome • Since early 1980s, > 500 transplants done • Considered the standard of care for Hurler • Donor-derived microglia engraft over 4-6 months, providing enzyme to the CNS • Enzyme infusions used for less severely effected patients (Scheie), as those without severe neurologic deterioration • Opportunity exists for combination therapy

24. Event-Free Survival Post HCT for Hurler’s Boelens JJ et al, Pediatr Clin of N. Am, 2010

25. Neuro Outcomes for Hurler’s The sooner the better! Mental = chronological age in 64% transplanted before age 2 Vs. Mental = chronological age in < 25% transplanted after age 2 P=0.01 Peters: Blood 1998: 91 (7) 2601-08

26. Unique Features for HCT for Metabolic Disorders • High risk for toxicity and mortality • High risk for rejection/ graft failure • Must balance these risks to achieve best outcomes • Full chimerism not needed to achieve clinical effect • Reduced-intensity regimens preferred in most patients • Related donors carriers of enzyme defect are not good donors. Unrelated cord blood preferred • Hard to measure effect of transplant on CNS manifestations • Many of the somatic symptoms do not improve after BMT, some may ‘worsen’ • Lack of data a big problem for insurance companies

27. Limitations of HCT for Rare Metabolic Disorders • Magic in numbers… • Rare nature of diseases and variation in severity limits the power of studies, ability to randomize, etc. • Well designed cooperative trials important, but limited resources, experience complicates assessments and outcome analysis • Growing interest in newborn screening may provide a chance to treat very early in the course of disease; cooperative trials may be important

28. HCT for Hemoglobinopathies • Sickle cell disease • Thalassemia major

29. Sickle cell disease World’s most common serious disease due to a single gene mutation Normal …..G A G G A G….. Sickle (6glu val) …..G T G G A G…..

30. Inheritance of Sickle Cell Disease • Autosomal recessive inheritance 2 parents with HgB S trait: 25% risk of child with SCD Not just in African Americans • African ancestry • Caribbean, Central/South America • Mediterranean (Greece, Italy) • Middle East • India

31. Sickling of Red Blood Cells • VASO-OCCLUSION • ANEMIA • HEMOLYSIS CLINICAL MANIFESTATIONS: Acute: - Painful crisis - Acute chest syndrome - Stroke - Splenic sequestration - Aplastic crisis - Priapism Chronic organ dysfunctions: - Spleen - Kidneys - Lungs: Pulmonary hypertension - Osteonecrosis - Eyes - Skin ulcers - Liver

32. Therapeutic Approaches for Sickle Cell Disease • Hydroxyurea (increase % fetal Hgb, decrease sickling) • Symptomatic management • Exchange transfusions and iron chelation therapy • Some patients may benefit from HCT - Recurrent pain crisis - Recurrent acute chest syndrome - CNS disease • Benefit of HCT decreases as age increases

33. Thalassemia Major • Inability to produce adequate amount of hemoglobin • Autosomal recessive inheritance • > African, Mediterranean, Asian descent • Chronic hemolytic anemia, poor growth, infections, bone deformities • Death, if untreated

34. Management of Thalassemia Major • Symptomatic management • Chronic transfusions and iron chelation therapy + splenectomy • Only known cure is HCT • Goal is to offer HCT early before chronic iron deposition causes end-organ damage

36. Matched Sibling HCT for Sickle Cell 93% 85% 9% Time (years) after BMT

37. Unrelated Donor HCT for Thalassemia Kaplan-Meier probabilities of survival, thalassemia-free survival, nonrejection mortality, and rejections for 32 thalassemia patients who received transplants from HLA-matched unrelated donors (parenthesis: 95% confidence limits at 2 years). La Nasa G et al. Blood 2002;99:4350-4356

38. Survival for Unrelated Cord Blood Transplantation for Hemoglobinopathies Sickle cell Thalassemia Ruggeri A, Eurocord, 2011

39. Unique Features of HCT for Hemoglobinopathies • High risk of rejection - Myeloablative conditioning is preferred • Many patients with end-organ damage cannot tolerate full conditioning  reduced intensity • Carrier relatives (HgB S trait) can be donors • Very small matched unrelated donor pool available Unrelated cord blood attractive, but risk of rejection high • Benefit of HCT decreases as age increases

40. Severe Aplastic Anemia (SAA) • Two of the following: • Neutrophils < 500/L (1500-5000) • Platelet count < 20 x 109/L (180-440) • Abs. reticulocyte count < 40 x 109/L (20-80) AND • Bone marrow biopsy < 25% cellularity Carmitta et al, Blood, 1976

41. Symptoms

42. Causes of Aplastic Anemia Inherited Acquired Pregnancy Drugs Infections Immune disorders Benzene Ionizing radiation Idiopathic • Fanconi anemia • Dyskeratosis congenita • Diamond Blackfan anemia • Shwachman-Diamond syndrome

43. Aplastic Anemia- Treatment • Supportive care • Immunosuppressive therapy • HCT

45. Probability of Overall Survival Kennedy-Nasser et al, Biol Blood Mar Transpl, 2006

46. Unique Features of Aplastic Anemia • May be able to use reduced conditioning • Related and Unrelated have similar outcomes • Try to transplant early • May need prolonged immunosuppression taper

47. Conclusions • Increasing use of HCT for non-malignant disorders • Donor/conditioning different depending on dz • Early consultation to HCT team for non-malignant dz

48. Thank You! Nycole Ferguson Shirley Mason Christina Burgin Julian Kern Meena Mishra Amanda Tuggle The Doernbecher Pediatric BMT Team • Eneida Nemecek, MD, MS • Bill Chang, MD, PhD • Peter Kurre, MD • Allison Franco, RN, BSN, CPHON • Erica Soler, RN, PNP All the patients and families whose care we have been privileged to provide