STEM CELL TRANSPLANT IN PEDIATRICS. Erin Meyer, DO, MPH Medical Director, Apheresis Nationwide Children s Hospital Columbus, OH 5/6/17

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1 STEM CELL TRANSPLANT IN PEDIATRICS Erin Meyer, DO, MPH Medical Director, Apheresis Nationwide Children s Hospital Columbus, OH 5/6/17

2 Disclosures Nothing to Disclose

3 Overview Stem Cell Transplant History Adult and Pediatrics CD34 enumeration Timing is everything Adverse Events in Pediatric HPC-A Future Directions

4 Stem Cell Transplant: Brief History

5 Brief History of BMT Atomic bombs dropped: 8/6/1945 and 8/9/1945 Bomb victims who survived initially later died from radiation induced bone marrow failure 1949 Mice exposed to normally lethal radiation survived when spleens are shielded (later marrow shielded) Postulations: Cellular vs. Humoral (non-cellular) hypothesis Late 1940s-1950s Protection due to transplantable hematopoietic stem cells Jacobson LO, et al. J Lab Clin Med Main JM, Prem RT. J Natl Cancer Inst Storb R. Pediatric Transplantation 2004.

6 Brief History of BMT 1985 C-CSF discovered Early 1980s Continuous flow leukocytapheresis to collect progenitor cells Appelbaum FR. NEJM 2007.

7 Historic Pediatric BMT Dr. E. Donnall Thomas Stem cell transplant pioneer 1 st to show radiation and chemotherapy followed by infusion of bone marrow 2 pediatric patients with leukemia Each had identical twin to serve as donor of normal isologous marrow Thomas et al. J Clin Invest 1959.

8 Sources of HPCs Bone Marrow (HPC, Marrow) Peripheral Blood (HPC, Apheresis) Umbilical Cord Blood (HPC, Cord Blood) Source Posterior iliac crest primarily; less commonly anterior iliac crest or sternum Collected after mobilization with recombinant hematopoietic growth factor and/or chemotherapy Collected at time of delivery Dose 2-5 x 10 8 stem cells/kg 2 x10 6 stem cells/kg x10 7 stem cells/kg Engraftment Faster than cord but less than peripheral blood Fastest Slowest T cell Content Low Highest (high risk of GVHD) Low and immature Other Commonly used in pediatric patients Commonly used in adults and autologous Mainly for allogeneic; rising use in pediatric and adult

9 Diseases Amendable to BMT Pediatric Autologous High-risk neuroblastoma Ewing sarcoma Relapsed retinoblastoma Germ cell tumors Wilms tumor Allogeneic 55% for AML or ALL 41% Nonmalignant Hemolgobinopathies Metabolic Storage Disorders Primary Immunodeficiencies Copelan EA. NEJM 2006.

10 2015 Guidelines from American Society for Blood and Marrow Transplantation

11 D'Souza A, Zhu X. Current Uses and Outcomes of Hematopoietic Cell Transplantation (HCT): CIBMTR Summary Slides, Available at:

12 CIBMTR: Stem Cell Sources in Pediatric Allogeneic HSCT Khandelwal P, et al. Biol Blood and Marrow Transplant 2017.

13 NCH Statistics % Autologous Transplants % Allogeneic Transplants % 61% 58% % 39% 42%

14 NCH Statistics: Indications for BMT Allogeneic Transplants AML (any type): 21% ALL (any type): 13% Autologous Transplants Medulloblastoma: 11% Neuroblastoma: 12%

15 Nationwide Children s Hospital Statistics: HPC-A HPC-M HPC-C Figure: Stem cell sources of 131 patients receiving 179 transplants

16 CD34 Counts

17 CD34 CD34 marker of hematopoietic progenitor cells and endothelial cells Circulate at low levels in peripheral blood May be mobilized into peripheral blood by cytokines Predict adequacy of HPC-A better than WBC: Armitage S, et al. Bone Marrow Transplantation 1997.

18 Timing is everything! Chemokine mobilization: Granulocytecolony stimulating factor (G-CSF) Standard mobilizing agent Non-chemo-mobilization transplant: Start G-CSF (Day 0) Collect via apheresis Day 4-5 Optimal collections: CD34+ cells 10 cells/μl (range 5-20 cells/μl)

19 Bendall LJ and Bradstock KF. Cytokine and Growth Factor Reviews 2014.

20 Chemomobilization us_stem_cell_collection.pdf

21 Mid-Point CD34 Testing We need to get enough stem cells to get this kid through treatment, okay? Pediatrics large volume leukapheresis can be challenging Venous access Smaller TBV Immature organs Staying still!

22 Mid-point CD34+ Testing Pre-Procedure CD34 in peripheral blood is predictive of CD34 yield in product Would mid-procedure CD34 count off product be helpful? Sidhu et al donors (autologous and allogeneic) 76 HPC-A collections 68 Adequate data Goal: same day collection with LV leukapheresis Process 5 TBV Check CD34 on product after 2.5 TBV processed Schlenke et al. Vox Sanguinis Sidhu et al. JCA 2006.

23 Sidhu et al. JCA 2006.

24 Adverse Events in Pediatric HPC-A

25 Adverse Events in Pediatric Apheresis Vascular Access: Peripheral vs. Central Temporary vs. Permanent Single vs. Double lumen Extracorporeal issues Replacement Fluid: Albumin Plasma or RBC (citrate %) Other Patient Factors: Total blood volume Red cell volume Coagulation status Disease specific considerations Cardio/pulmonary status Fluid status Renal status Transfusion reactions Technical Considerations: Extracorporeal volume Lower inlet flow rates Continuous vs. discontinuous Choice/dosing of anticoagulant Prime: RBCs or other Blood warmer Diversion/ Rinseback Meyer, EK and Wong, ECC. Transfusion Medicine Reviews 2016.

26 Adverse Events in Pediatric Apheresis Meyer, EK and Wong, ECC. Transfusion Medicine Reviews 2016.

27 Adverse Events Pediatric HPC-A Healthy pediatric donors sibling donors recruited for 39-48% of all childhood transplantations Bone marrow is still standard of care worldwide PB is increasing Procedural differences in collection of each! VS Pasquini M, Wang Z. Current use and outcome of hematopoietic stem cell transplantation: CIBMTR Summary Slides. Available at Styczynski J, et al. Transplantation

28 European Group for Blood and Marrow Transplantation Pediatric Diseases Working Party Study Prospective, multicenter observational study practice on sibling donor collections (<18 years old) HPC-M Harvest Outcomes Incidence and severity of pain Anemia Blood allotransfusion CV disturbances Complications after anesthesia Prolonged Hospital stay (>2 days post) HPC-A Collection Outcomes Complications of anesthesia for CVC placement Incidence of pain during G-CSF administration and collection Incidence of symptomatic hypocalcemia Number of apheresis procedures Prolonged hospital stay (>1 day post) Styczynski J, et al. Transplantation 2012.

29 Styczynski J, et al. Transplantation 2012.

30 Styczynski J, et al. Transplantation 2012.

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33 AE: Autologous donors?? HPC-A X Adverse Event(s) Confounders Underlying disease Underlying treatment course

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35 Cooling L, et al. JCA 2017.

36 Procedure-Related Complications and AE: Pediatric Autos <18 yo autologous donors AE related to: Citrate anticoagulation Venous Access Technical Issues Other 62 children underwent 110 procedures 72% had neuroblastoma or CNS tumor Target: million CD34+/kg for three stem cell rescues 61% collected a single procedure Cooling L, et al. JCA 2017.

37 Cooling L, et al. JCA 2017.

38 Overall 39% Overall 48% Cooling L, et al. JCA 2017.

39 NCH Experience: Patients: 45 Procedures: 59 AE: 20% of procedures (12/59) Access Issue: 58% Clotted CVC Bleeding Technical Issue: 25% Slow Inlet Unstable interface Other: 17% Fever Increased BP 17% 25% 58% Access Issue Technical Issue Other

40 Future Directions

41 Future Directions Cellular Therapy CAR-T Haploidential BMT ASFA Pediatric Subcommittee Adverse Events Study

42 CAR T Immunotherapy Chimeric antigen receptor (CAR)-modified T cells targeting lineage-specific CD19 and CD20 effective in adults with CLL and B-cell lymphomas Use in pediatrics relapsed and chemotherapy refractory pre-b ALL Genetically modify a patient s T cells so that it recognizes and can kill tumor B cells but not other cells Requires 3-4 TBV leukapheresis procedure Patient needs to have: ALC of at least 500 CD3 count of at least 200 Till BG, et al. Blood Porter DL, et al. NEJM 2011 Grupp SA et al. NEJM 2013.

43 Haploidentical Transplants Allogeneic-BMT is first line for: Recurrent/Refractory hematologic malignancies Bone marrow failure Immunodeficiency Hemoglobinopathy Metabolic Disorders Ideal donor: HLA-matched sibling (MSD) Increased evidence of equivalent outcomes: HLA-matched unrelated donor volunteer (MUD) 10/10 match at: HLA-A, -B, -C, -DRβ1, -DQβ1

44 Haploidentical Transplants Haploidentical donors provide comparable outcomes to MSD or MUD 5/10 match at HLA-A, -B, -C, -DRβ1, -DQβ1 i.e. Parent! Graft source: follow disease and clinical indications Predominately HPC-Marrow HPC-Apheresis when indicated

45 EBMT 2015 Report Passweg JR, et al. Bone Marrow Transplantation 2017.

46 ASFA Pediatric AE Prospective Study Prospective, Observational, Multi-Center, International Study Clinical, Access, Technical AE Gather in a consistent manner REDCap Database Participating Sites: Seattle Children s Boston Children s Children s Hospital of Philadelphia Nationwide Children s Hospital Emory/Children s Healthcare of Atlanta Children s Hospital Colorado Ann and Robert H. Lurie Children s Hospital of Chicago Children s Hospital of Los Angeles University of North Carolina Phoenix Children s Hospital Hospital de Pediatria Garrahan, Argentina Washington University/St. Louis Children s Hospital Children s National Medical Center

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51 My Amazing Apheresis Team!

52 Questions please!