Cynthia Simpson Vanessa Spaw

1. Cynthia Simpson Vanessa Spaw Stem Cell Therapy

2. Objectives • To provide a basic introduction to stem cell research and therapy • Give an overview of the pediatric conditions in which hematopoietic stem cell therapy is a treatment • To discuss hematopoietic stem cell transplantation (HSCT) in children with leukemia 

3. Basic Information • Embryonic stem cells are being used in research to see how they can be manipulated to create different tissues • Hematopoietic stem cells “adult stem cells”can come from bone marrow, peripheral blood, or umbilical cord blood • In 2007, specialized adult somatic cells called induced pluripotent stem cells (iPSC) were discovered • Stem cells can differentiate into different types of tissue • Replace diseased and damaged tissues in the body

4. Research is currently being done with embryonic stem cells to develop treatment Cancers Diabetes Cardiac failure Muscle damage Neurological disorders Most hematopoietic stem cell treatments are still in the experimental stage A lot of new research recently started with iPSC Induced pluripotent stem cells Research

5. Controversy & Politics • Ethical issue surrounding the use of stem cells from embryos • In 2001, the US government instituted a ban on Federal funding toward research that used embryonic stem cells • This ban was recently lifted; embryonic stem cells can now be harvested for federally funded research

6. Diverse research is happening in different body system areas An appreciation for the possibilities Research

7. Endless Possibilities • Growing nerve cell clusters on bioengineered scaffolding  • Creating new cardiac tissue from iPSC cells • iPSC cells reprogrammed into beta-type cells that produce insulin

8. Pediatric Stem Cell Therapy • Nervous System (Neuroblastoma, Autism) • Musculoskeletal (Muscular Dystrophy) • Organ generation (viable fetal kidney for in-utero transplantation)

9. Conditions affecting bone, blood, & lymph Hematopoietic cancers Leukemia CA marrow/blood Multiple myeloma CA of plasma Lymphoma Hodgkin's Osteosarcoma Blood Sickle cell anemia B-thalassemia Metabolic storage diseases Bone Osteogenesisimperfecta (OI) HSCT Treatment for Pediatrics

10. Allogenic Donor with matching tissue type Immune system suppression therapy Chemotherapy Risk of graft-versus-host disease & infection Autologous Extraction and storage of stem cells from patient Chemotherapy Replacement of stem cells Lower risk of infection/rejection Hematopoietic Stem Cell Transplantation

11. Malignant disease of the bone marrow and blood Result of an acquired genetic injury to the DNA of a single cell Malignant & multiplies continuously Accumulation of these cells interferes with the body's production of healthy blood cells What is Leukemia?

12. How Many are Effected? • 33% of cancers in children ages 0-14 years are leukemia • Leukemia, lymphoma, & myeloma account for nearly 9.6% of the new cancer cases diagnosed in the US in 2008 • These cancers also accounted for 9.4% deaths from cancer in 2008 • That's ~53,000 people.

13. Acute Lymphocytic Leukemia Chronic Lymphocytic Leukemia Acute Myelogenous Leukemia Chronic Myelogenous Leukemia Types of Leukemia

14. Blood work Bone Marrow Biopsy Other diagnostic procedures Diagnosis

15. Bone Marrow Biopsy

16. Patient Presentation     Male 4 year old with constant low grade fever for 2 days and cough. PCP recommended fluids and close monitoring. After 2 weeks of constant fever and persistent cough, PCP orders blood work • The Results: Elevated WBC, elevated monocytes, and decreased RBC count. 1 week before diagnosis

17. Diagnosis • Juvenile Myelomonocytic Leukemia (JMML) • Serious chronic leukemia • Mostly children aged 4 and under • Average age of diagnosis is 2 First week in the hospital

18. Treatment • No accepted protocol for treatment • Two protocols most widely used for study • Children’s Oncology Group • The European Working Group for Myelodysplastic Sydromes • Other options: HSCT, Chemotherapy, Radiation Therapy, and Splenectomy • Only HSCT has been shown to have curative effects on JMML

19. Treatment 4 weeks of steroids, 15 pound weight gain

20. Prognosis • With HSCT there is about a 50% chance of event free survival • Three characteristics have been shown to be best predictors of positive outcomes • Male • Diagnosis before age 2 • Diagnosis of Noonan’s Syndrome • Genetic congenital syndrome

21. Complications • Immediate side effects of procedure • Nausea, vomiting, diarrhea, & mouth sores • Infections due to immune suppression • Toxicities produced by multiple medications • Graft-versus-host disease • T-lymphocytes react against the transplanted cells • Recurrence

22. Physical Therapy • Infection control • Handwashing is crucial • Treatment environment • Avoid fatigue • Articular symptoms • Mood changes & irritability • Improve quality of life • Make therapy FUN & FUNctional • Other contraindications?

23. Keep Them Moving & Smiling

24. NCMRR • Pathology • Juvenile Myelomonocytic Leukemia • Impairment • Fatigue, decreased strength, weight gain, immunosuppression • Functional limitation • Difficulty with community ambulation due to fatigue & decreased physical activity • Disability • Unable to attend school!!! Or other indoor pubic venues • Societal limitation • Child will have limited options to play with peers, hair loss & weight gain stigma

25. Hematopoietic Stem Cell Transplantation in Children with Juvenile Myelomonocytic Leukemia: Results of the EWOG-MDS/EBMT TrialLocatelli, F. et al. • 67 boys & 33 girls • Diagnosis of Juvenile Myeolomonocytic Leukemia • Preparatory therapy before HSCT • Allogenic graft from a donor • HLA typing: histo-compatibility

26. Results • Mean time to platelet recovery was 18 days • At 100 days tissue biopsies showed 40% had graft-versus-host disease (GVHD) • Compared event-free survival rates with two previous studies on HSCT  • 49% to 55% 5 year event-free survival as compared to earlier studies of 24% & 38% • Disease recurrence is the major cause of death • Stats look grim, but an large increase in event-free survival is hopeful indicator for future research

27. Take Home Message • Stem cell research is just at its beginning…. Possibilities! • Stem cell therapies are making progress & shown to be improving outcomes. • As a PT it’s important to be aware of these advancements to provide optimum care to our patients who have received stem cell therapy treatments.

28. QUESTIONS

29. References • Gupta, DK et al. Stem cell therapy: Hope and scope in pediatric practice. J of Indian Assoc Pediatric Surgey. 2005:10;138-41. • Locatelli F et al. Hematopoietic Stem Cell Transpantation in Children with Juvenile Myelomonocytic Leukemia: Results of the EWOG_MDS/EBMT Trial. Blood. 2005:105;410-419. • Oringanje et al. Hematopoietic Stem Cell Transpantation in Children with Sickle Cell Disease. Cochrane database of Sytematic reviews. 2009:1; Art. no. CD007001. • Stem cell Transplantation. Dana-Farber Cancer institute. Avaible at :Http:// dana-farber.org/pediatric-care. Accessed 3/31/2009. • Gluckman E. Hematopoietic stem-cell transplants using umbilical-cord blood. N Engl J Med. 2001;344:1860-1861. • Martino R. et al. Evidence for a graft-versus-leukemia effect after allogeneic perifpheral blood stem cell transplantation with reduced-intensity conditioning in actue myelogenous leukemia and myelodysplastic syndromes. Blood J. 2002;100:2243-2245. • Korbling M. Allogeneic blood stem cell transplantation for refractory leukemia and lymphoma: Potential advantage of blood over marrow allografts. Blood J. 1995;85:1659-1665. • Leukemia & Lymphoma Society. Disease information: Facts & statistics. 2008. Available at: http://www.leukemia-lymphoma.org/all_page?item_id=12486. Accessed April 6, 2009. • Goodman C, Fuller K, Boissonnault W. Pathology: Implications for the Physical Therapist. Pennsylvania. Saunders. 2003. • Rodgers C. Growth patterns and gastrointestinal symptoms in pediatric patients after hematopoietic stem cell transplantaion. Oncology Nursing Forum. 2008;35:443-448. • Eisenberg S. Hepatic sinusoidal obstruction syndrome in patients undergoing hematopoietic stem cell transplant. Oncology Nursing Forum. 2008;35:385-397.