ELECTRONIC SUPPLEMENT

APPENDIX E1

PIDTC LEADERSHIP WORKSHOP, BETHESDA, MD, APRIL 19-20, 2015

Steering Committee

Morton J. Cowan, MD, Division of Allergy/Immunology and Blood and Marrow Transplantation, Department of Pediatrics and UCSF Benioff Children’s Hospital, University of California San Francisco, San Francisco, CA

Linda M. Griffith, MD, MHS, PhD, Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD

Donald B. Kohn, MD, Departments of Microbiology, Immunology & Molecular Genetics and Pediatrics, University of California Los Angeles, Los Angeles, CA

Luigi D. Notarangelo, MD, Division of Immunology, Children’s Hospital, and Harvard Stem Cell Institute, Harvard Medical School, Boston, MA

Jennifer M. Puck, MD, Institute for Human Genetics, and Division of Allergy/Immunology and Blood and Marrow Transplantation, Department of Pediatrics and UCSF Benioff Children’s Hospital, University of California San Francisco, San Francisco, CA

Additional Discussants

Marcia Boyle, Immune Deficiency Foundation, Towson, MD

Rebecca H. Buckley, MD, Pediatric Allergy and Immunology, Duke University School of Medicine, Durham, NC

Lauri M. Burroughs, MD, Pediatric Hematology/Oncology, Fred Hutchinson Cancer Research Center, University of Washington School of Medicine, Seattle, WA

Elizabeth Dunn, MA, Pediatric Allergy/Immunology and Blood and Marrow Transplant Division, UCSF Benioff Children’s Hospital, University of California, San Francisco, CA

Christopher C. Dvorak, MD, Pediatric Allergy/Immunology and Blood and Marrow Transplant Division, UCSF Benioff Children’s Hospital, University of California, San Francisco, CA

Thomas A. Fleisher, MD, Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD

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Elie Haddad, MD, PhD, Pediatric Immunology and Pediatrics, Mother and Child Ste-Justine Hospital, University of Montreal, Montreal, QC, Canada

Elizabeth M. Kang, MD, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD

Brent R. Logan, PhD, Center for International Blood and Marrow Transplant Research and Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI

Harry L. Malech, MD, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD

James G. McNamara, MD, Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD

Richard J. O'Reilly, MD, Pediatrics and Immunology, Memorial Sloan Kettering Cancer Center, New York, NY

Sung-Yun Pai, MD, Pediatric Hematology/Oncology, Children’s Hospital, Harvard Medical School, Boston, MA

Robertson Parkman, MD, Blood and Marrow Transplantation, Lucille Packard Children’s Hospital, Stanford University School of Medicine, Stanford, CA

Michael A. Pulsipher, MD, Children’s Center for Cancer and Blood Diseases, Pediatric Hematology/Oncology, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA

William T. Shearer, MD, PhD, Pediatric Allergy & Immunology, Texas Children's Hospital, Baylor College of Medicine, Houston TX

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APPENDIX E2

PIDTC ANNUAL SCIENTIFIC WORKSHOPS - HOUSTON, TX, MAY 2-4, 2013 (THIRD); SEATTLE, WA, MAY 1-3, 2014 (FOURTH); AND MONTREAL, QUEBEC, CANADA, APRIL 30 - MAY 2, 2015 (FIFTH), WITH EDUCATION DAY, APRIL 29-30, 2015

Workshop Co-Chairs and Local Organizing Committees

Lauri M. Burroughs, MD, Pediatric Hematology/Oncology, Fred Hutchinson Cancer Research Center, University of Washington School of Medicine, Seattle, WA (Seattle, WA, 2014)

Morton J. Cowan, MD, Division of Allergy/Immunology and Blood and Marrow Transplantation, Department of Pediatrics and UCSF Benioff Children’s Hospital, University of California San Francisco, San Francisco, CA

Hélène Decaluwe, MD, PhD, Pediatric Immunology and Pediatrics, Mother and Child Ste-Justine Hospital, University of Montreal, Montreal, QC, Canada (Montreal, Canada, 2015)

Linda M. Griffith, MD, MHS, PhD, Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD

Elie Haddad, MD, PhD, Pediatric Immunology and Pediatrics, Mother and Child Ste-Justine Hospital, University of Montreal, Montreal, QC, Canada (Montreal, Canada, 2015)

Donald B. Kohn, MD, Departments of Microbiology, Immunology & Molecular Genetics and Pediatrics, University of California Los Angeles, Los Angeles, CA

Luigi D. Notarangelo, MD, Division of Immunology, Children’s Hospital, and Harvard Stem Cell Institute, Harvard Medical School, Boston, MA

Jennifer M. Puck, MD, Institute for Human Genetics, and Division of Allergy/Immunology and Blood and Marrow Transplantation, Department of Pediatrics and UCSF Benioff Children’s Hospital, University of California San Francisco, San Francisco, CA

William T. Shearer, MD, PhD, Pediatric Allergy & Immunology, Texas Children's Hospital, Baylor College of Medicine, Houston TX (Houston, TX, 2013)

Troy R. Torgerson, MD, PhD, Pediatric Rheumatology, Seattle Children’s Research Institute, University of Washington School of Medicine, Seattle, WA (Seattle, WA, 2014)

Invited Speakers

Roshini S. Abraham, PhD, Department of Laboratory Medicine and Pathology, Mayo College of Medicine, Rochester, MN

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Michael H. Albert, MD, Department of Hematology and Oncology, Munich Children’s Hospital, Munich, Germany

Barbara Ballard, Immune Deficiency Foundation, Towson, MD

Carmem Bonfim, MD, Bone Marrow Transplantation Center, Federal University of Parana, Curitiba, Brazil

Marcia Boyle, Immune Deficiency Foundation, Towson, MD

Malcolm K. Brenner, MD, PhD, Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX

Amy Brower, PhD, Newborn Screening Translational Research Network, American College of Medical Genetics and Genomics, Bethesda, MD

Rebecca H. Buckley, MD, Pediatric Allergy and Immunology, Duke University School of Medicine, Durham, NC

Frederick D. Bushman, PhD, Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA

Jayanta Chaudhuri, PhD, Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY

Charlotte Cunningham-Rundles, MD, PhD, Pediatric Clinical Immunology, Mount Sinai School of Medicine, New York, NY

Carole Ann Demaret, The David Center, Texas Children’s Hospital, Houston, TX

Morna J. Dorsey, MD, MMSc, Pediatric Immunology and Allergy Center, Department of Pediatrics and UCSF Benioff Children’s Hospital, University of California San Francisco, San Francisco, CA

Christopher C. Dvorak, MD, Pediatric Allergy/Immunology and Blood and Marrow Transplant Division, UCSF Benioff Children’s Hospital, University of California, San Francisco, CA

Alain Fischer, MD, PhD, National Health Institute of Medical Research (INSERM) and Department of Pediatric Immunology, Necker Hospital, Paris France

Thomas A. Fleisher, MD, Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD

Danielle N. Friedman, MD, Pediatric Long-Term Follow-Up Program, Memorial Sloan-Kettering Cancer Center, New York, NY

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Ephraim J. Fuchs, MD, Department of Hematology and Oncology, Johns Hopkins University School of Medicine, Baltimore, MD

Andrew R. Gennery, MD, Institute of Cellular Medicine, Great North Children’s Hospital, Newcastle University, Newcastle upon Tyne, UK

Georg A. Hollander, MD, Department of Biomedicine, University of Basel, Switzerland

Emily Hovermale, Immune Deficiency Foundation, Towson, MD

Alan Hurley, Chronic Granulomatous Disease Association, San Marino, CA

Mary Hurley, Chronic Granulomatous Disease Association, San Marino, CA

Kohsuke Imai, MD, PhD, Department of Pediatrics, Tokyo Medical and Dental University, Tokyo, Japan

Sumathi Iyengar, MD, Wiskott-Aldrich Foundation, Inc., Smyrna, GA

Elizabeth M. Kang, MD, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD

Jeffrey Krischer, PhD, Division of Bioinformatics and Biostatistics, Department of Pediatrics, University of South Florida College of Medicine, Tampa, FL

Franco Locatelli, MD, PhD, Pediatric Hematology/Oncology and Transfusion Medicine, Bambino Gesu Children’s Hospital, Rome, Italy

Brent R. Logan, PhD, Center for International Blood and Marrow Transplant Research and Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI

James R. Lupski, MD, PhD, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX

Harry L. Malech, MD, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD

M. Louise Markert, MD, PhD, Pediatric Division of Allergy and Immunology, Duke University School of Medicine, Durham, NC

Fred Modell, Jeffrey Modell Foundation, New York, NY

Vicki Modell, Jeffrey Modell Foundation, New York, NY

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Hans Ochs, DM, Center for Immunity and Immunotherapy, Seattle Children’s Hospital Research Institute, University of Washington School of Medicine, Seattle, WA

Jordan S. Orange, MD, PhD Immunology, Allergy and Rheumatology, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX

Richard J. O'Reilly, MD, Pediatrics and Immunology, Memorial Sloan Kettering Cancer Center, New York, NY

Sung-Yun Pai, MD, Pediatric Hematology/Oncology, Children’s Hospital, Harvard Medical School, Boston, MA

Elena E. Perez, MD, PhD, Pediatric Allergy and Immunology, Batchelor Research Institute, University of Miami School of Medicine, Miami, FL

Claude Perreault, MD, Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Canada

Matthew H. Porteus, MD, PhD, Pediatric Hematology/Oncology, Lucile Packard Children’s Hospital, Stanford University School of Medicine, Stanford, CA

Michael A. Pulsipher, MD, Children’s Center for Cancer and Blood Diseases, Pediatric Hematology/Oncology, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA

David J. Rawlings, MD, Pediatric Immunology, Seattle Children’s Research Institute, University of Washington School of Medicine, Seattle, WA

Maria-Grazia Roncarolo, MD, Division of Pediatric Translational and Regenerative Medicine, Institute for Stem Cell Biology and Regenerative Medicine, Lucille Packard Children’s Hospital, Stanford University School of Medicine, Stanford, CA

Christopher Scalchunes, Immune Deficiency Foundation, Towson, MD

Judith Shizuru, MD, PhD, Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, Stanford, CA

Heather Smith, SCID Angels for Life Foundation, Lakeland, FL

Robert Sokolic, MD, Office of Cell Tissue and Gene Therapies, CBER, FDA, Silver Spring, MD

Ricardo Sorensen, MD, Department of Pediatrics, Children’s Hospital, LSU School of Medicine, New Orleans, LA

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Paul Szabolcs, MD, Bone Marrow Transplantation and Cellular Therapies, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA

Claudia Wehr, MD, Center for Chronic Immunodeficiency, University Medical Center Freiburg and the University of Freiburg, Freiburg, Germany

Irving Weissman, MD, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA

Additional Discussants

Jordan Abbott, MA, MD, Pediatric Allergy and Clinical Immunology, National Jewish Health, Denver, CO

Rolla F. Abu-Arja, MD, Pediatric Hematology/Oncology, Nationwide Children’s Hospital, Columbus, OH

Stephanie Albin, MD, Pediatrics, Children’s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA

Doerthe Adriana Andreae, MD, Pediatrics, Mount Sinai Hospital, New York, NY

Victor Aquino, MD, Pediatric Hematology-Oncology, University of Texas Southwestern, Dallas, TX

Rosa Bachetta, MD, Division of Pediatric Translational and Regenerative Medicine, Institute for Stem Cell Biology and Regenerative Medicine, Lucille Packard Children’s Hospital, Stanford University School of Medicine, Stanford, CA

K. Scott Baker, MD, MS, Fred Hutchinson Cancer Research Center Survivorship Program, and Pediatric Blood and Marrow Transplant, Seattle Children’s Hospital and University of Washington, Seattle, WA

Bezhad B. Bidadi, MD, Pediatric Hematology/Oncology, Mayo Clinic, Rochester, MN

Henrique Bittencourt, MD, Pediatric Hematology/Oncology, Mother and Child Ste-Justine Hospital, Montreal, Quebec, Canada

Jeffrey J. Bednarski, MD, PhD, Pediatric Hematology/Oncology, St. Louis Children’s Hospital, Washington University School of Medicine, St. Louis, MO

Jack J. H. Bleesing, MD, PhD, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati,OH

Richard J. Bram, MD, PhD, Pediatric Immunology, Mayo Clinic, Rochester, MN

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Nancy J. Bunin, MD, Pediatric Hematology/Oncology, Children’s Hospital of Philadelphia, Philadelphia, PA

Jessica Carlson, Pediatric Allergy/Immunology and Blood and Marrow Transplant Division, UCSF Benioff Children’s Hospital, University of California, San Francisco, CA

Sonia Cellot, MD, Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Canada

Alice Chan, MD, Pediatric Allergy/Immunology and Rheumatology, UCSF Benioff Children’s Hospital, University of California San Francisco, CA

Ka Wah Chan, MD, Pediatric Blood and Marrow Transplant, Methodist Hospital/Texas Transplant Institute, University of Texas Health Science Center, San Antonio, TX

Joseph H. Chewning II, MD, Pediatric Hematology/Oncology, University of Alabama, Birmingham, AL

Hey Jin Chong, MD, PhD, Pediatric Allergy and Immunology, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA

Julia I. Chu, MD, Pediatric Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, MA

James Albert Connelly, MD, Pediatric Hematology/Oncology, C. S. Mott Children’s Hospital, University of Michigan, Ann Arbor, MI

Guilhem Cros, MD, Pediatric Immunology and Pediatrics, Mother and Child Ste Justine Hospital, University of Montreal, Montreal, QC, Canada

Geoff Cuvelier, MD, Pediatric Hematology/Oncology, University of Manitoba, Manitoba, Canada

Blachy Davila-Saldana, MD, Pediatric Hematology/Oncology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH

Jean-Jacques De Bruycker, MD, Pediatric Immunology and Pediatrics, Mother and Child Ste Justine Hospital, University of Montreal, Montreal, QC, Canada

Yesim Demirdag, MD, Pediatric Allergy and Immunology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY

Suk See De Ravin, MD, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD

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Elizabeth Dunn, MA, Pediatric Allergy/Immunology and Blood and Marrow Transplant Division, UCSF Benioff Children’s Hospital, University of California, San Francisco, CA

Michel Duval, MD, Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Centre, and Pediatric Hematology / Oncology, Ste Justine Hospital, University of Montreal, Montreal, QC, Canada

Alexandra H. Filipovich, MD, Pediatric Clinical Immunology, Division of Hematology / Oncology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH

Matthew Fletcher, MD, Pediatric Hematology/Oncology, Oschner Medical Center, New Orleans, LA

Lisa R. Forbes, MD, Pediatric Allergy/Immunology, Children’s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA

Ramsay L. Fuleihan, MD, Allergy/Immunology, Lurie Children’s Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL

Erwin W. Gelfand, MD, Pediatric Allergy and Immunology, National Jewish Hospital, National Jewish Health, Denver, CO

Alfred P. Gillio, MD, Pediatric Hematology/Oncology, Hackensack University Medical Center, Hackensack, NJ

Frederick Goldman, MD, Blood and Marrow Transplant, and Pediatric Hematology/Oncology, Children’s Hospital of Alabama, University of Alabama School of Medicine, Birmingham, AL

Eyal Grunebaum, MD, Pediatric Immunology/Allergy and Bone Marrow Transplantation, The Hospital for Sick Children, University of Toronto, Ontario, Canada

Erin K. Ham, MD, Allergy and Immunology, Seattle Children’s Hospital, University of Washington, Seattle, WA

Laura Hancock, Children’s Oncology Group Operations Center, Monrovia, CA

Imelda Celine Hanson, MD, Pediatric Allergy/Immunology, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX

Jennifer R. Heimall, MD, Pediatric Allergy/Immunology, Children’s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA

Rosalie Helfrich, Division of Bioinformatics and Biostatistics, Department of Pediatrics, University of South Florida College of Medicine, Tampa, FL

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Avni Y. Joshi, MD, Pediatric Allergy-Immunology and Infectious Diseases, Mayo Clinic, Rochester, MN

Neena Kapoor, MD, Division of Research Immunology/Blood and Marrow Transplant, Children’s Hospital of Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA

Michael D. Keller, MD, Pediatric Allergy and Immunology, Children’s National Medical Center, Washington, DC

Shakila P. Khan, MD, Pediatric Blood and Marrow Transplantation, and Hematology/Oncology, Mayo Clinic, Rochester, MN

Vy Kim, MD, Pediatric Allergy and Immunology, Hospital for Sick Children, University of Toronto, Ontario, Canada

Morris Kletzel, MD, Pediatric Hematology/Oncology, Lurie Children’s Memorial Hospital, Northwestern University School of Medicine, Chicago, IL

Alan P. Knutsen, MD, Pediatric Allergy/Immunology, Cardinal Glennon Children’s Hospital, St. Louis University School of Medicine, St. Louis, MO

Z. Yesim Kucuk, MD, Pediatric Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH

Caroline Y. Kuo, MD, Pediatric Allergy and Immunology, University of California Los Angeles, CA

Antonia Kwan, PhD, MRCPCH, Pediatrics, University of California San Francisco, CA

Jennifer W. Leiding, MD, Pediatric Allergy and Immunology, All Children’s Hospital, University of South Florida, Tampa, FL

Lisa Lim, Seattle Cancer Care Alliance Network, Fred Hutchinson Cancer Research Center, Seattle, WA

Janel R. Long-Boyle, PharmD, PhD, Department of Clinical Pharmacy, School of Pharmacy, University of California, San Francisco, CA

Julia Lopes-Garcia, Pediatric Hematology / Oncology, Ste Justine Hospital, University of Montreal, Montreal, QC, Canada

Reza Macaraeg, Seattle Cancer Care Alliance Network, Fred Hutchinson Cancer Research Center, Seattle, WA

Paul J. Maglione, MD, PhD, Allergy and Immunology, Mount Sinai Hospital, New York, NY

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Rebecca A. Marsh, MD, Pediatric Hematology/Oncology, Cincinnati Children’s Hospital, Cincinnati, OH

Caridad Martinez, MD, Pediatric Hematology/Oncology, Texas Children’s Cancer Center, Baylor College of Medicine, Houston, TX

Bhakti Mehta, MD, Pediatric Hematology/Oncology, Children’s Hospital of Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA

Alexandra (Xanne) Miggelbrink, Boston Children’s Hospital, Harvard Medical School, Boston, MA

Holly Miller, MD, Pediatric Hematology/Oncology, Mott Children’s Hospital, University of Michigan, Ann Arbor, MI

Theodore B. Moore, MD, Pediatric Hematology/Oncology, UCLA Medical Center, University of California, Los Angeles, CA

Maria Teresa de la Morena, MD, Pediatric Allergy/Immunology, Children’s Medical Center, University of Texas Southwestern, Dallas, TX

Megan M. Morsheimer, MD, Pediatrics, UCSF Benioff Children’s Hospital, University of California San Francisco, CA

Hana B. Niebur, MD, Pediatric Allergy and Immunology, All Children’s Hospital, University of South Florida, Tampa, FL

Omar Niss, MD, Pediatric Hematology/Oncology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH

Satiro de Oliveira, MD, Pediatric Hematology/Oncology, UCLA Medical Center, University of California, Los Angeles, CA

Suhag H. Parikh, MD, Pediatric Blood and Marrow Transplantation, Duke University Medical Center, Durham, NC

Kenneth Paris, MD, Pediatric Allergy/Immunology, Children’s Hospital of New Orleans, Louisiana State University Health Sciences Center, New Orleans, LA

Robertson Parkman, MD, Blood and Marrow Transplantation, Lucille Packard Children’s Hospital, Stanford University School of Medicine, Stanford, CA

Kiran P. Patel, MD, Pediatric Allergy and Immunology, UCSF Benioff Children’s Hospital, University of California San Francisco, CA

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Aleksandra Petrovic, MD, Pediatric Hematology/Oncology, All Children’s Hospital, St Petersburg, FL

Susan Eliza Prockop, MD, Pediatric Hematology/Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY

Divya Punwani, MD, Pediatric Allergy and Immunology, UCSF Benioff Children’s Hospital, University of California, San Francisco, CA

Troy C. Quigg, DO, MS, Pediatric Hematology/Oncology, Methodist Children’s Hospital, Texas Transplant Institute, San Antonio, TX

Jo-Anne Richer, BSN, Pediatric Oncology, Mother and Child Ste-Justine Hospital, Montreal, Quebec, Canada

Nicholas L. Rider, DO, Pediatric Allergy and Immunology, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX

John M. Routes, MD, Pediatric Allergy and Clinical Immunology, Children’s Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, WI

Jacob Rozmus, MD, Pathology and Laboratory Medicine, BC Children’s Hospital, University of British Columbia, Vancouver, BC, Canada

Holly Ruhlig, Data Management and Coordinating Center, Rare Diseases Clinical Research Network, Division of Bioinformatics and Biostatistics, Department of Pediatrics, University of South Florida College of Medicine, Tampa, FL

Blythe D. Sather, PhD, Department of Immunology, Seattle Children’s Hospital and University of Washington, Seattle, WA

Marlis Schroeder, MD, Pediatric Hematology/Oncology, Faculty of Medicine, University of Manitoba, Canada

Heather L. Schuback, MD, Pediatric Hematology/Oncology, Seattle Children’s Hospital and University of Washington, Seattle, WA

Kirk R. Schultz, MD, Pediatric Hematology/Oncology and Transplantation, BC Children’s Hospital, University of British Columbia, Vancouver, BC, Canada

Silvia Selleri, PhD, Department of Pediatrics, Mother and Child Ste-Justine Hospital, Montreal, Quebec, Canada

Christine M. Seroogy, MD, Pediatric Allergy and Immunology, University of Wisconsin Children’s Hospital, Madison, WI

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Evan B. Shereck, MD, Pediatric Hematology/Oncology, Doernbecher Children’s Hospital, Oregon Health & Science University, Portland, OR

Suzanne Skoda-Smith, MD, Pediatric Allergy/Immunology, Seattle Children’s Research Institute, University of Washington School of Medicine, Seattle, WA

Trudy N. Small, MD, Pediatric Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, NY

Angela Smith, MD, MS, Pediatric Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN

Bryce Corey Smithson, MD, Pediatrics, Children’s Hospital of Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA

Heather Stefanski, MD, PhD, Pediatric Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN

Mary Stoelinga, APN, NP, Pediatric Hematology/Oncology, Lurie Children’s Hospital, Chicago, IL

Kathleen E. Sullivan, MD, PhD, Pediatric Immunology, Children’s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA

Ho Yan Herman Tam, MD, Manitoba Institute of Child Health, Winnipeg, Canada

Agne Taraseviciute, MD, Pediatric Hematology/Oncology, Seattle Children’s Hospital and University of Washington, Seattle, WA

Katherine G. Tarlock, MD, Pediatric Hematology/Oncology, Seattle Children’s Hospital and University of Washington, Seattle, WA

Teresa K. Tarrant, MD, Rheumatology, Allergy and Immunology, University of North Carolina, Chapel Hill, NC

Pierre Teira, MD, Pediatric Hematology/Oncology, Mother and Child Ste-Justine Hospital, Montreal, Quebec, Canada

Monica Thakar, MD, Pediatric Bone Marrow Transplant, Children’s Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, WI

Marie-France Vachon, RN, MScN, Mother and Child Ste-Justine Hospital, Montreal, Quebec, Canada

Mark T. Vander Lugt, MD, Pediatric Hematology/Oncology, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, PA

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Jet van der Spek, Boston Children’s Hospital, Harvard Medical School, Boston, MA

Paul Veys, MD, Blood and Marrow Transplantation, Institute of Child Health, Great Ormond Street Hospital, London, UK

Katja G. Weinacht, MD, PhD, Pediatric Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, MA

Sheila Weiss, MS, Washington State Newborn Screening Laboratory, Department of Health, Shoreline, WA

Lisa C. Winterroth, MD, Pediatric Allergy and Immunology, Seattle Children’s Hospital and University of Washington, Seattle, WA

Ann E. Woolfrey, MD, Pediatric Hematology/Oncology, Seattle Children’s Hospital, Fred Hutchinson Cancer Research Center and University of Washington, Seattle, WA

Joyce E. Yu, MD, Pediatric Allergy and Immunology, New York-Presbyterian Hospital, Columbia University Medical Center, New York, NY

Lolie C. Yu, MD, MPH, Pediatric Hematology/Oncology, Children’s Hospital, LSU School of Medicine, New Orleans, LA

Cecilia R. Zapata, MS, Seattle Cancer Care Alliance Network, Fred Hutchinson Cancer Research Center, Seattle, WA

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ELECTRONIC SUPPLEMENT REFERENCES

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E2. Hacein-Bey Abina S, Pai SY, Gaspar HB, Armant M, Berry CC, Blanche S, et al. A modified gamma-retrovirus vector for X-linked severe combined immunodeficiency. New Engl J Med. 2014; 371: 1407-1417.

E3. Zhou S, Ma Z, Lu T, Janke L, Gray JT, Sorrentino BP. Mouse transplant models for evaluating the oncogenic risk of a self-inactivating XSCID lentiviral vector. PLoS One. 2013; 8(4): e62333.

E4. De Ravin SS, Gray JT, Throm RE, Spindler J, Kearney M, Wu X, et al. False-positive HIV PCR test following ex vivo lentiviral gene transfer treatment of X-linked severe combined immunodeficiency vector. Mol Ther. 2014; 22: 244-245.

E5. Candotti F, Shaw KL, Muul L, Carbonaro D, Sokolic R, Choi C, et al. Gene therapy for adenosine deaminase-deficient severe combined immune deficiency: clinical comparison of retroviral vectors and treatment plans. Blood. 2012; 120: 3635-3646.

E6. Gaspar HB. Gene therapy for ADA-SCID: defining the factors for a successful outcome. Blood. 2012; 120: 3628-3629.

E7. Carbonaro Sarracino D, Tarantal AF, Lee CC, Martinez M, Jin X, Wang X, et al. Effects of vector backbone and pseudotype on lentiviral vector-mediated gene transfer: studies in infant ADA-deficient mice and rhesus monkeys. Mol Ther. 2014; 22: 1803-1816.

E8. Santilli G, Almarza E, Brendel C, Choi U, Beilin C, Blundell MP, et al. Biochemical correction of X-CGD by a novel chimeric promoter regulating high levels of transgene expression in myeloid cells. Mol Ther. 2011; 19: 122-132.

E9. Aiuti A, Biasco L, Scaramuzza S, Ferrua F, Cicalese MP, Baricordi C, et al. Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome. Science. 2013; 341: 1233151.

E10. Bosticardo M, Ferrua F, Cavazzana M, Aiuti A. Gene therapy for Wiskott-Aldrich syndrome. Curr Gene Ther. 2014; 14: 413-421.

E11. Hacein-Bey Abina S, Gaspar HB, Blondeau J, Caccavelli L, Charrier S, Buckland K, et al. Outcomes following gene therapy in patients with severe Wiskott-Aldrich syndrome. JAMA. 2015; 313: 1550-1563.

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640641642643

644645646647

648649650651

652653654

655656657658

659660661

Table E6 References

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667668669670671672673674

675676677678679680681682683684685686687688689690691692693694695696697698699700701702703704705

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E57. Ouachee-Chardin M, Elie C, de Saint Basile G, Le Deist F, Mahlaoui N, Picard C, et al. Hematopoietic stem cell transplantation in hemophagocytic lymphohistiocytosis: a single-center report of 48 patients. Pediatrics 2006; 117: e743-e750.

E58. Marsh RA, Vaughn G, Kim MO, Li D, Jodele S, Joshi S, Mehta PA, et al. Reduced-intensity conditioning significantly improves survival of patients with hemophagocytic lymphohistiocytosis undergoing allogeneic hematopoietic cell transplantation. Blood 2010; 116: 5824-5831.

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E60. Marsh RA, Bleesing JJ, Chandrakasan S, Jordan MB, Davies SM, Filipovich AH. Reduced-intensity conditioning hematopoietic cell transplantation is an effective treatment for patients with SLAM-associated protein deficiency / X-linked lymphoproliferative disease type 1. Biol Blood Marrow Transplant. 2014; 20: 1641-1645.

E61. Shah S, Wu E, Rao VK, Tarrant TK. Autoimmune lymphoproliferative syndrome: an update and review of the literature. Curr Allergy Asthma Rep 2014; 14: 462.

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E63. Dimopoulou MN, Gandhi S, Ghevaert C, Chakraverty R, Fielding A, Webster D, et al. Successful treatment of autoimmune lymphoproliferative syndrome and refractory autoimmune thrombocytopenic purpura with a reduced intensity conditioning stem cell transplantation followed by donor lymphocyte infusion. Bone Marrow Transplant 2007; 40: 605-606.

E64. Sleight BJ, Prasad VS, DeLaat C, Steele P, Ballard E, Arceci RJ, et al. correction of autoimmune lymphoproliferative syndrome by bone marrow transplantation. Bone Marrow Transplant 1998; 22: 375-380.

E65. Benkerrou M, Le Deist F, de Villartay JP, Caillat-Zucman S. Rieux-Laucat F, Jabado N, et al. Correction of Fas (CD95) deficiency by haploidentical bone marrow transplantation. Eur J Immunol 1997; 27: 2043-2047.

E66. d’Hennezel E, Bin Dhuban K, Torgerson T, Piccirillo CA. The immunogenetics of immune dysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome. J Med Genet 2012; 49: 291-302.

E67. Barzaghi F, Passerini L, Bacchetta R. Immune dysregulation, polyendocrinopathy, enteropathy, x-linked syndrome: a paradigm of immunodeficiency with autoimmunity. Front Immunol 2012; 3: 211.

E68. Horino S, Sasahara Y, Sato M, Niizuma H, Kumaki S, Abukawa D, et al. Selective expansion of donor-derived regulatory T cells after allogeneic bone marrow transplantation in a patient with IPEX syndrome. Pediatr Transplant 2014; 18: E25-E30.

E69. Burroughs LM, Storb R, Leisenring WM, Pulsipher MA, Loken MR, Torgerson TR, et al. Intensive postgrafting immune suppression combined with nonmyeloablative conditioning for transplantation of HLA-identical hematopoietic cell grafts: results of a pilot study for treatment of primary immunodeficiency disorders. Bone Marrow Transplant. 2007; 40: 633-642.

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888889890891892893894895896897898899900901902903904905906907908909910911912913914915916917918919920921922923924925926927928929930931932933

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22

934935936937938939940941942943944945946947948949950951952953954955956957958959960961962963964965966967968969

TABLE E1. PIDTC PROTOCOLS AND CUMULATIVE ENROLLMENTProtocol 6901 (SCID Prospective)

Year, January 1 – December 31 2010 2011 2012 2013 2014 2015 (through June 30)

TOTAL CUMULATIVE

Sites newly approved (opened) for study participation (per year)

6 13 6 7 1 0 33

Sites submitting potential patients (cumulative)

3 12 19 24 27 29 29

Patients submitted to PIDTC-SCID RP (per year

6 24 35 44 40 24 173

Subjects enrolled / approved by PIDTC-SCID RP (per year; see note)

6 21 36 38 40 27 168

Patients deemed ineligible by PIDTC-SCID RP

0 0 1 3 1 0 5

V1.0 – 19 May 2010; V2.0 – 10 February 2011; V3.0 – 28 August 2012From 19 May 2010, 33 North American PIDTC sites were eligible to participate in 6901; beginning 9/2014, 42 centers are eligible.Note: Patients reviewed in a given year may be approved for enrollment during the same year or the subsequent year, depending on the timeframe of the review process.

Protocol 6902 (SCID Retrospective)Year, January 1 – December 31 2011 2012 2013 2014 2015 (through

June 30)TOTAL CUMULATIVE

Sites newly approved (opened) for study participation (per year)

16 11 5 1 0 33

Sites submitting potential patients (cumulative)

16 27 33 33 33 33

Patients submitted to PIDTC-SCID RP (per year)

209 240 205 180 1 835

Subjects enrolled / approved by PIDTC-SCID RP (per year; see note)

201 191 174 155 6 727

Patients deemed ineligible by PIDTC-SCID RP

3 38 38 23 5 107

V1.0 – 30 November, 2010; V2.0 – 8 February 2012; V3.0 – 29 August 2012 From 30 November 2010, 33 North American PIDTC sites were eligible to participate in 6902; beginning September 2014, 42 sites are eligible. Note: Patients reviewed in a given year may be approved for enrollment during the same year or the subsequent year, depending on the timeframe of the review process.

Protocol 6902 (SCID XS)Subjects enrolled on the XS study are a subset of those previously enrolled and surviving,

on the retrospective study.Year, January 1 – December 31 2011 2012 2013 2014 2015 (through

June 30)TOTAL CUMULATIVE

Sites submitting potential patients (cumulative)

2 6 13 18 19 19

Subjects enrolled /signed 6902 XS consent (per year)

27 28 25 13 6 100

V1.0 – 30 November, 2010; V2.0 – 8 February 2012; V3.0 – 29 August 2012 From 30 November 2010, 33 North American PIDTC sites were eligible to participate in 6902; beginning September 2014, 42 sites are eligible. XS, Cross-Sectional

23

970

971972973974975

976

977978979980981982

983984985986

Protocol 6903 (CGD)Year, January 1 – December 31 2014 2015 (through

June 30)TOTAL CUMULATIVE

Sites newly approved (opened) for study participation (per year) 9 18 27Sites submitting potential patients (cumulative) 1 9 9Patients submitted to PIDTC-CGD RP (per year) 2 77 79Subjects enrolled / approved by PIDTC-CGD RP (per year) 2 68 70Patients deemed ineligible by PIDTC-CGD RP 0 0 0V1.0 – 23 December 2013From 23 December 2013, 33 North American PIDTC sites were eligible to participate in 6903; beginning September 2014, the total is 45 sites; 42 of these are North American, and 3 are European.Note: Patients reviewed in a given year may be approved for enrollment during the same year or the subsequent year, depending on the timeframe of the review process.

Protocol 6904 (WAS)Year, January 1 – December 31 2014 2015 (through

June 30)TOTAL CUMULATIVE

Sites newly approved (opened) for study participation (per year) 16 13 29Sites submitting potential patients (cumulative) 3 11 11Patients submitted to PIDTC-WAS RP (per year) NA 21 21Subjects enrolled / approved by WAS-SCID RP (per year) NA 21 21Patients deemed ineligible by PIDTC-WAS RP 0 0V1.0 - 28 October 2013From 28 October 2013, 33 North American PIDTC sites were eligible to participate in 6904; beginning September 2014, 42 sites are eligible.Note: Patients reviewed in a given year may be approved for enrollment during the same year or the subsequent year, depending on the timeframe of the review process. NA, not applicable.

24

987

988989990991992993

994

995996997998999

10001001100210031004

TABLE E2.Goals and Significance of PIDTC Workshops

Sponsor Workshop (Reference) Goals and SignificancePIDTC Workshop Debate2013

Radiation-sensitive severe combined immunodeficiency: the arguments for and against conditioning before hematopoietic cell transplantation – what to do? (Cowan MJ, Gennery AR. J Allergy Clin Immunol. 2015; 136: 1178-1185.)

Defects in DNA repair pathways which recognize and repair nonprogrammed DNA double-strand breaks (DSBs) have potential to compromise genomic integrity, and result in radiation-sensitive SCID. For some of these genotypes, exposure to alkylator therapy also appears to be associated with decreased survival and late effects remain to be determined for all of these disease types. At the same time, alklyators have potential to increase donor chimerism and T-cell and B-cell reconsititution. This thoughtful discussion considers best approaches to HCT for this challenging group of SCID pateints.

PIDTC Workshops, 2011 & 2012

Primary Immune Deficiency Treatment Consortium (PIDTC) report. (Griffith LM, Cowan MJ, Notarangelo LD, et al. J Allergy Clin Immunol. 2014; 133: 335-347.)

The PIDTC is a network of 33 centers in North America that care for patients with PID. The objectives and progress to date of PIDTC natural history protocols are summarized. Other goals of the PIDTC include: training of young investigators, establish partnerships with International colleagues, work with patient advocacy groups to promote community awareness, and conduct pilot demonstration projects. PIDTC Annual Scientific Workshops of 2011 and 2012 are summarized. Future consortium objectives are considered.

PIDTC Workshop Debate2012

B-cell reconstitution for SCID: should a conditioning regimen be used in SCID treatment? (Haddad E, Leroy S, Buckley RH.J Allergy Clin Immunol. 2013; 131: 994-1000.)

Reconstitution of T-cells is reliably achieved following allogeneic HCT for SCID, whereas reconstitution of B-cells is problematic. Factors important for B-cell reconstitution include genotype of the SCID defect, and use of a conditioning regimen containing busulfan. The risks and benefits of conditioning to achieve B-cell reconstitution are considered.

PIDTC Practice Survey2011

Survey on re-transplantation criteria for patients with severe combined immunodeficiency. (Haddad E, Allakhverdi, Z, Griffith LM, Cowan MJ, Notarangelo LD. J Allergy Clin Immunol. 2014; 133: 597-599.)

In spite of their immunodeficiency, patients with SCID may experience graft loss or failure to engraft following allogeneic HCT, especially given the goal to use no or minimal conditioning in these vulnerable young patients. The criteria used to define failure of HCT and decide when to re-transplant are summarized.

NIH - NIAID & ORDR, NCATSWorkshop 2009

Improving cellular therapy for primary immune deficiency diseases: recognition, diagnosis, and management. (Griffith LM, Cowan MJ, Notarangelo LD, Puck JM, Buckley RH, Candotti F, et al. J

PIDTC investigators assembled their collective expertise in management of patients with PIDs before, during and after HCT, to develop guidance documents for their colleagues who care for these patients.

25

1005

Allergy Clin Immunol. 2009; 124: 1152-1160.e12.)

NIH - NIAID & ORDR, NCATSWorkshop 2008

Allogeneic hematopoietic cell transplantation for primary immune deficiency diseases: current status and critical needs. (Griffith LM, Cowan MJ, Kohn DB, Notarangelo LD, Puck JM, Schultz KR, et al. J Allergy Clin Immunol. 2008; 122: 1087-1096.)

Determine feasibility of natural history studies to evaluate outcomes of HCT for PID in North America, identify expertise needed to undertake such investigations, and propose key diseases and research questions. Although allogeneic HCT has been used to treat PID for 40 years, this is the first effort to organize a collaborative review of outcomes in North America. PID selected for the initial studies include SCID, chronic granulomatous disease, and Wiskott-Aldrich syndrome. Investigator collaborations established due to this workshop have served as a foundation for PIDTC.

26

1006100710081009

1010

TABLE E3. PIDTC Pilot Project Awards

Award Year

Investigator and Institution

Project PIDTC Presentation (Year) and/or Publication

2009-2011

Jennifer Puck MD, UCSF, San Francisco, CA

SCID diagnosed by newborn screening in Navajo Native Americans.

Presentation (2011, 2012, 2014)Publication: Kwan A, Hu D, Song M, et al. Successful newborn screening for SCID in the Navajo Nation. Clin Immunol. 2015; 158: 29-34.

2012-2013

Sung-Yun Pai MD, Childrens Hospital of Boston, Boston, MA

Recovery of CD19+ B-cell development and function after hematopoietic stem cell transplant for SCID.

Presentation (2014)

2014 Hélène Decaluwe MD, PhD, and Francoise Le Deist, MD, Mother and Child Ste-Justine Hospital, Montreal, QC, Canada

T cell exhaustion in SCID after hematopoietic stem cell transplant

Presentation (2014, 2015)

2015-2016

David Rawlings MD, Seattle Children’s Hospital, Seattle, WA

Investigation of the molecular and cellular mechanisms of autoimmunity in patients with Wiskott-Aldrich syndrome undergoing hematopoietic stem cell transplant

Presentation (2015)

27

1011

10121013

TABLE E4. PIDTC Fellowship Awards

Award Year

Investigator and Institution

PIDTC Workshop Presentation (Year) and Publication

2009 Shirley Becker-Herman, PhD, Seattle Children’s Research Institute, Seattle, WA

Presentation: NAPublication: Becker-Herman S, Meyer-Bahlburg A, Schwartz MA, Jackson SW, Hudkins KL, Liu C, et al. WASp-deficient B cells play a critical, cell-intrinsic role in triggering autoimmunity. J Exp Med. 2011; 208: 2033-2042.

2009 Theodore Johnson MD,PhD; Cincinnati Children’s Hospital Medical Center, Cincinnati, OH

Presentation (2011): The mechanism of etoposide activity in hemophagocytic lymphohistiocytosisPublication: Johnson TS, Terrell CE, Millen SH, Katz JD, Hildeman DA, Jordan MB. Etoposide selectively ablates activated T cells to control the immunoregulatory disorder hemophagocytic lymphohistiocytosis. J Immunol. 2014; 192: 84-91.

2010 Soma Jyonouchi MD; Childrens Hospital of Philadelphia, PA

Presentation (2011): Immunodeficiency relational database

Database: www.immunodeficiencysearch.com

2010 Heather Stefanski MD,PhD; University of Minnesota Medical Center, Minneapolis, MN

Presentation (2011): Utilizing T progenitors to improve immune reconstitution in primary immunodeficiencyPublication: Taylor PA, Kelly RM, Bade ND, Smith MJ, Stefanski HE, Blazar BR. FTY720 markedly increases alloengraftment but does not eliminate host anti-donor T cells that cause graft rejection on its withdrawal. Biol Blood Marrow Transplant. 2012; 18: 1341-1352.

2011 Lisa Forbes MD; Baylor College of Medicine, Houston, TX

Presentation (2012): Dendritic cell activation and migration after allergen challenge in CGD mice

2011 Jacob Rozmus MD; BC Childrens Hospital, Vancouver, BC, Canada

Presentation (2012): Using biomarkers to help us better understand the pathophysiology of chronic graft-versus-host disease

Publication: Rozmus J, Mallhi K, Ke J, Schultz KR. Functional hyposplenism after hematopoietic stem cell transplantation. Bone Marrow Transplant. 2015; 50: 1343-1347.

2012 Silvia Selleri MD; CHU Ste-Justine, Montreal, Quebec, Canada

Presentation (2013): Mesenchymal cells modulation of immune regulation of monocytes, macrophages and dendritic cellsPublication: Selleri S, Dieng MM, Nicoletti S, Louis I, Beausejour C, Le Deist F, Haddad E. Cord-blood-derived mesenchymal stromal cells downmodulate CD4+ T-cell activation by inducing IL-10-producing Th1 cells. Stem Cells Dev. 2013; 22: 1063-1075.

2012 Omar Niss MBBS; Cincinnati Children’s Hospital Medical Center, Cincinnati, OH

Presentation (2013): Dysregulated BCL-2 pathway in autoimmune lymphoproliferative syndrome (ALPS)Publication: Niss O, Sholl A, Bleesing JJ, Hildeman DA. IL-10/Janus kinase/signal transducer and activator of

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transcription 3 signaling dysregulates Bim expression in autoimmune lymphoproliferative syndrome. J Allergy Clin Immunol. 2015; 135: 762-770.

2012-2013

Katja Weinacht MD,PhD; Children’s Hospital Boston, Harvard Medical School, Boston, MA

Presentations (2013, 2014): Disease modeling for reticular dysgenesis (mutation of AK2 gene) with induced pluripotent stem cells (iPS)Publication: Rissone A, Weinacht K, la Marca G, Bishop K, Giocaliere E, Jagadeesh J et al. Reticular dysgenesis-associated AK2 protects hematopoietic stem and progenitor cell development from oxidative stress. J Exp Med. 2015; 212: 1185-1202.

2012-2013 and 2014

Caroline Kuo MD; UCLA Mattel Childrens Hospital, Los Angeles, CA

Presentations (2013. 2014, 2015): Targeted gene therapy in the treatment of X-linked hyper-IgM syndrome (CD40 ligand deficiency) using TALENS

2014 Teresa Tarrant MD; University of North Carolina School of Medicine, Chapel Hill, NC

Presentation (2015): Interrogating genetic susceptibility loci in CVID with autoimmunityPublication: Burbank AJ, Shah SN, Montgomery M, Peden D, Tarrant T, Weimer ET. Clinically focused exome sequencing identifies a homozygous mutation that confers DOCK8 deficiency. Pediatr Allergy Immunol. 2015; August 1 [Epub ahead of print].

2015 Julia I Chu, MD; Children’s Hospital, University of Minnesota School of Medicine, Minneapolis, MN

Presentation (2015): Development of a gene therapy model for DOCK 8 deficiency

2015 Paul Maglione, MD; Icahn School of Medicine at Mount Sinai, New York, NY

Presentation (2015): Elucidating the role of BAFF in CVID interstitial lung disease

Note: NA, not applicable.

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TABLE E5. Gene Transfer Studies in PID Currently Open and Planned

XSCID Center Sponsor(s) Vector Treatment Regimen

Publications

“XSCID-2” Includes Parallel EU Study

Activation Date: 2011; recruiting

Registration:ClinicalTrials.gov NCT01129544 (London & Paris);ClinicalTrials.govNCT01175239 (Boston, Cincinnati, Los Angeles).

Parallel European and North American studies.US: Boston, Cincinnati, Los Angeles;EU: London, Paris.

US Funding: NIAID(D. Williams).

UK: NHS Foundation Trust (A. Thrasher)

FR: Assistance Publique-Hopitaux Paris (A. Fischer)

Virus: Gamma retrovirus, deleted of LTR enhancer elements, with transgene expression mediated by a cellular promoter.Insert: IL2R gamma chainModifications: WPRE post-translational regulatory element to enhance expressionSafety modifications: EFS (EF1 alpha short) cellular internal promoter; U3 deletion in LTR (SIN configuration)Vector development: C. Baum,Hannover, Germany Vector manufacture: CincinnatiTarget: BM CD34+ cells

US IND: D. Williams, Children’s Hospital Boston

Conditioning: None

References: Zychlinski et al (2008),E1 Hacien-Bey Abina et al (2014)E2

Activation Date: 2012 recruiting

Registration:ClinicalTrials.gov NCT01512888

St. Jude, Memphis, TN

Funding: NHLBI (B. Sorrentino)

Virus: LentivirusInsert: IL2R gamma chainSafety modifications: EFS (EF1 alpha short) cellular internal promoter; U3 deletion in LTR (SIN configuration); enhancer blocking insulator sequence(s)Vector development: St. Jude-B. SorrentinoTarget: BM CD34+ cells

Conditioning: None initially; modified for low dose busulfan

References: Zhou et al (2013)E3

Proposed “XSCID-3” Includes Parallel EU Study

Activation Date:In development

Parallel European and North American studies. US: Boston Children’s Hospital; UC Los Angeles.EU: Great Ormond Street Hospital, London; Zurich; and Leiden.

Proposed US Funding: NIAID (S.-Y. Pai)

UK: NHS Foundation Trust (A. Thrasher)

Switzerland: Pending

Netherlands: Pending

Virus: LentivirusInsert: IL2R gamma chainSafety modifications: EFS (EF1 short) cellular internal promoter; U3 deletion in LTR (SIN configuration);enhancer blocking insulator sequence(s)Vector manufacture: Genethon, Paris, FRTarget: BM CD34+ cells

US IND: D. Williams, Children’s Hospital BostonEU IND: EU will have a separate regulatory package, and Genethon will hold the EU IND.

Conditioning: Propose to include reduced intensity conditioning

References:This study will be the next generation study to follow Hacien-Bey-Abina et al (2014)E2

XSCID in Older Children

Center Sponsor(s) Vector Treatment Regimen

Publications

Activation Date: 2010, recruiting

NIH Clinical Center /Intramural

Funding: NIH Clinical Center & Intramural

Virus: LentivirusInsert: IL2R gamma chainSafety modifications: EFS

Conditioning: Busulfan 6mg/kg

References:De Ravin et al (2014)E4

30

1017

Registration:Clinical Trials.govNCT01306019

NIAID NIAID(S. S. DeRavin, H. Malech)

(EF1 short) cellular internal promoter; U3 deletion in LTR (SIN configuration);enhancer blocking insulator sequence(s)Target: CD34+ mPBSCVector development: St. Jude -B. Sorrentino

ADA SCID Center Sponsor(s) Vector Treatment Regimen

Publications

Activation Date: May 2013Recruiting

Registration:ClinicalTrials.govNCT01852071

UCLA, NIH Clinical Center /Intramural NHGRI

US and London UK are parallel studies (see below).

Funding: NIAID (D. Kohn)

Virus: LentivirusInsert: ADA geneModifications: codon optimized human ADA cDNA, WPRE post-translational regulatory element to enhance expressionSafety modifications: EFS (EF1 alpha short) cellular internal promoter; U3 enhancer deletion in LTR (SIN configuration)Vector manufacture: IUVPFTarget: BM CD34+ cells

PEG-ADA: Discontinue day +30.Conditioning: Myeloreductive Busulfan (4 mg/kg)

References:Candotti et al (2012),E5 Gaspar (2012),E6

Carbonaro-Sarracino (2014)E7

Activation Date: 2012Recruiting

Registration:ClinicalTrials.govNCT01279720

London GOSH, UK

US and London UK are parallel studies (see above).

UK: NHS Foundation Trust (A. Thrasher)

Virus: LentivirusModifications: codon optimized human ADA cDNA, WPRE post-translational regulatory element to enhance expressionSafety modifications: EFS (EF1 alpha short) cellular internal promoter; U3 enhancer deletion in LTR (SIN configuration)Vector manufacture: IUVPFTarget: BM CD34+ cells; if > 5 kg mobilize PBSC

PEG-ADA: Discontinue day +30Conditioning: Myeloreductive Busulfan (4 mg/kg)

References:Gaspar (2012),E6

Carbonaro-Sarracino et al (2014)E7

ProposedActivation Date:In development

This will be a phase 3 licensure study

UC Los Angeles; London

US and London, UK will be parallel studies

US Funding: NIAID(D. Kohn).

UK: NHS Foundation Trust (A. Thrasher)

Virus: LentivirusModifications: codon optimized human ADA cDNA, WPRE post-translational regulatory element to enhance expressionSafety modifications: EFS (EF1 short) cellular internal promoter; U3 enhancer deletion in LTR (SIN configuration)Vector manufacture: IUVPFTarget: BM CD34+ cells; if > 5 kg mobilize PBSC

Orphan Drug Registration status for vector received from FDA October 2014

PEG-ADA: Discontinue day +30.Conditioning: Myelo-reductive Busulfan (4 mg/kg).

References:This will be the licensure study, to follow the studies immediately above.

XCGD Center Sponsor(s) Vector Treatment Regimen

Publications

Proposed US Study

Activation Date:

UC Los Angeles; NIH Clinical Center

Proposed US Funding: CIRM (D. Kohn); NIH Clinical Center &

Virus: LentivirusInsert: gp91phoxSafety modifications: Regulated promoter (chimeric

Conditioning: pK targeted Busulfan

References:Santilli G et al (2011)E8

31

In development /Intramural NIAID, Bethesda;Boston Children’s Hospital.

US and EU subjects will be a combined safety database.

Intramural NIAID(E. Kang/H. Malech)

CatG/cFes promoter with mutated TATA box contains binding sites for transcription factors needed for commitment & differentiation myeloid cells to granulocyte lineage)Vector manufacture: Genethon, Paris, FRTarget: CD34+ mPBSC

US: D. Kohn, UC Los Angeles - IND approved by FDA as of November 2014, and will open protocol in January 2015Graft Manufacture in US: DFCI GMP facility is lead and will train & qualify other sites

Proposed EU Study – Parallel to US Study

Activation Date:In development

4 sites - Germany; London, UK; Zurich, Switzerland; and Paris, France.

EU & US studies parallel & independent.

EU funding

UK: NHS Foundation Trust (A. Thrasher)

Virus: LentivirusInsert: gp91phoxSafety modifications: Regulated promoter (chimeric CatG/cFes promoter with mutated TATA box contains binding sites for transcription factors needed for commitment & differentiation myeloid cells to granulocyte lineage)Vector manufacture: Genethon, Paris, FR. New European vector construct will be the same for the EU and US studies.Target: CD34+ mPBSC

Conditioning: pK targeted Busulfan

References:Santilli G et al (2011)E8

WAS Center Sponsor(s) Vector Treatment Regimen

Publications

EU Study -Includes US Boston Site

Activation Date: 2010 (Milan); 2011 (London, Paris, Boston); recruiting

Registration:ClinicalTrials.govNCT01347242 (London);ClinicalTrials.govNCT01347346 (Paris)ClinicalTrials.govNCT01515462 (TIGET, Milan);ClinicalTrials.govNCT01410825 (Boston).

London, UK; Paris, France; Milan, Italy; Boston, USA

US funding for Boston site: GTRP, NHLBI(D. Williams)

UK: NHS Foundation Trust (A. Thrasher)

FR:Assistance Publique-Hopitaux Paris (A. Fischer); French National Registry for Primary Immuno-deficiencies; Genethon.

IT: Fondazione Telethon (TIGET core grant to A. Aiuti and others) and the European

Virus: LentivirusInsert: WASpModifications: WPRE post-translational regulatory element to enhance expressionSafety modifications: hWAS endogenous promoterVector manufacture: Genethon, Paris, FR;Target: CD34+ mPBSC

Pre-Conditioning: Anti-CD20 monoclonal Ab.Conditioning: Reduced intensity Busulfan 8-12 mg/kg, Fludarabine 120 mg/m2; ATG if autoimmune manifestations

References:Aiuti et al (2013),E9 Bosticardo et al (2014),E10

Hacein-Bey Abina et al(2015)E11

32

Commission (M.-G. Roncarolo, A. Aiuti and L. Naldini), Italian Ministero della Salute.

Notes:Retrovirus and lentivirus vectors are used in PID; adenovirus and AAV vectors are not persistent in proliferating bone marrow stem cells and lymphocytes (so cannot be used for GT for PID). The necessity to transfect CD34 ex vivo or lymphocytes ex vivo is cumbersome, but relatively effective.MLV = Moloney murine leukemia virus; MFG or MFGS = MLV vector with MLV LTR and MLV envelope splice acceptor site (Malech group); MND = MPSV LTR, negative control region deleted, dl587 primer binding site substituted (Kohn group); SF = or SFFV = spleen focus forming virus LTR. IUVPF = Indiana University Vector Production Facility, CIRM=California Institute for Regenerative Medicine.

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101810191020102110221023102410251026102710281029

TABLE E6.Emerging Indications for HCT in PID (Selected)

Indicationand

References

Disease Mechanism and

Clinical Features

Disease Incidence

HCT Outcomes

HCT Comments

Combined T Cell and B Cell ImmunodeficienciesSTAT1 GOF

Mutation:STAT1

References:Liu et al (2011)E12

AD STAT-1 GOF mutations impair nuclear dephosporylation of activated STAT-1 and thereby IL-17 immunity. Patients experience chronic mucocutaneous candidiasis and other infections, and autoimmunity.

Twelve (12) AD STAT-1 GOF mutations have been described E12

Four (4) patients have been transplanted (personal communication), all are surviving as of July 2015.

HCT appears to have clinical benefit.

Unclear if mixed chimerism is sufficient for resolution of infections.

STAT3 GOF

Mutation:STAT3

References:Milner et al (2015)E13

Mutations confer GOF in STAT-3 leading to secondary defects in STAT-5 and STAT-1 phosphorylation and the regulatory T-cell compartment. Patients experience infections and autoimmunity including type 1 diabetes, and autoimmune thyroid, pulmonary and arthritic disease.

Nine (9) different heterozygous mutations in STAT-3 have been described in 13 individuals from 10 families E13

Three (3) patients have received HCT (personal communication), all are surviving as of July 2015.

Patients have 80-100% donor chimerism and appear improved clinically.

HCT appears to have clinical benefit.

STAT3 LOF (AD- Hyper-IgE Syndrome (HIES) / Job Syndrome)

Mutation:STAT3

References:Wilson et al (2015)E14

LOF mutations in STAT3 cause reduced numbers of peripheral blood mucosal associated invariant T-cells and natural killer T-cells. Patients experience recurrent infections including cutaneous viral infections, abscesses and pulmonary complications, with characteristic skeletal abnormalities.

Multiple individuals having STAT-3 LOF have been described recently.E14

Five (5) patients have been transplanted (personal communication); all are surviving as of July 2015.

Four (4) of 5 patients have 95-100% donor chimerism, with improvement in clinical condition; 1 patient is recently post-HCT.

HCT appears to have clinical benefit.

IFNGR1 Autosomal Partial Dominant Deficiency (IFN Gamma Receptor-1)

Mutation:IFNGR1

References:Dorman et al (2004),E15

Sharma et al (2015)E16

Response to IFN-γ is impaired. Mutant protein is more stable than WT and does not signal. Patients are susceptible to BCG and environmental mycobacterial infections, including M. avium complex osteomyelitis.

Thirty-eight (38) patients with IFNGR1 partial dominant deficiencies have been identified and reviewed.E15 Additional cases have been described.E16

One (1) patient with course complicated by multifocal osteomyelitis due to M. para-scrofulaceum and marginal zone B-cell lymphoma is recently post-HCT as of July 2015; treatment for recurrent lymphoma has been needed (personal

HCT appears to have clinical benefit.

34

1030

communication).DOCK2 AR LOF (Dedicator of Cytokinesis 2)

Mutation:DOCK2

References:Dobbs et al (2015)E17

RAC1 activation is impaired in T-cells. Chemokine-induced activation and actin polymerization are defective in T-cells, B-cells, and NK-cells, and NK-cell degranulation is affected. Due to lymphopenia and defective T-cell, B-cell and NK-cell responses, children develop early-onset invasive bacterial and viral infections. Early diagnosis is critical.

Five (5) unrelated children with this genetic defect have recently been described.E17

Three (3) of the 5 patients described received HCT and are well; the other 2 did not receive HCT and died in early childhood.E17

HCT appears potentially curative.

DOCK8 Deficiency (Dedicator of Cytokinesis 8)

Mutation:DOCK8

References:Aydin et al (2015),E18

Cuellar-Rodriguez et al (2015),E19 Notarangelo (2013)E20

AR hyper-IgE syndrome with CID is a cellular immunodeficiency. The underlying CID affects B-cells, NK cells, and CD8 subsets of T-cells. Patients are predisposed to cutaneous viral infections; complications including severe life-threatening infections, malignancy and stroke constitute severe morbidity and adversely affect mortality.

One hundred thirty-six (136) patients have recently been examined in an international retrospective surveyE18

Of the 136 patients reported, 36 patients received HCT and detailed analysis is underway; other reports of treatment with HCT are referenced. E18 HCT for an additional 6 patients has recently been reported. E19

Consideration of early HCT is recommended as a potential curative measure.

CARD-11(CARMA-1) AR LOF (Caspase Recruitment Domain Family, Member 11)

Mutation:CARD11

References:Turvey et al (2014)E21

Stepensky et al (2013)E22

CARD-11 is a member of the CBM signalosome complex which also includes BCL-10 and MALT-1. E21 Germline mutations of the CBM complex cause novel CID phenotypes with abnormal NFkB activation after B-cell and T-cell antigen receptor stimulation. Patients have normal T cell numbers with abnormal proliferation, absence of regulatory T –cells, and dysregulated B cell development. CARD-11deficient patients experience severe CID with early onset hypogammaglobulinemia and PjP. Note, TREC-based NBS may fail to identify affected individuals.

Three (3) patients in 2 families having germline mutation of CARD-11 have been reported. E21

All 3 patients have received curative HCT. E21

Early therapeutic allogeneic HCT is recommended.

BCL-10 AR LOF (B-cell CLL / Lymphoma 10)

Mutation:BCL10

References:Torres et al (2014)E23

BCL-10 is a member of the CBM signalosome complex. Normal T cell numbers with abnormal proliferation, dysregulated B cell development, and fibroblast defects may be present.

A single case has been reported. E23

One patient has been described; the patient did not receive HCT.

Based on BCL-10 biology, restoration of immune function by HCT should be possible.

MALT-1 AR LOF MALT-1 is a member of the Three (3) cases are One (1) patient Based on

35

(Mucosa Associated Lymphoid Tissue Lymphoma TranslocationGene-1)

Mutation:MALT1

References:Turvey et al (2014),E21

Jabara et al (2013),E24 McKinnon et al (2014),E25

Punwani et al (2015)E26

CBM signalosome complex. Patients have normal T cell numbers with abnormal proliferation, and dysregulated B cell development. MALT-1 deficient patients experience severe CID with gastrointestinal inflammation. Note, TREC-based NBS may fail to identify affected individuals. TCR stimulation-induced proliferation, and additional specific tests should be pursued.

reviewed;E21,E24,E25 and 1 case is reported.E26

has received successful HCT.E26

MALT-1 biology, restoration of immune function by HCT should be possible.

IKK2 / IKKBeta AR LOF (IKK2 SCID)

Mutation:IKBKB

References:Pannicke et al (2013),E27

Burns et al (2014),E28

Nielsen et al (2014),E29

Mousallem et al (2014),E30

Senegas et al (2015)E31

IKK-2 is a component of the IKK-nuclear factor kB (NF-kB) pathway. B-cell and T-cell counts are normal, almost exclusively of naïve phenotype, and have impaired responses to mitogens. Patients have hypogammaglobulinemia / agammaglobulinemia and early onset of severe infections.

Four (4) patients from 4 families of Northern Cree, E27 1 patient from the Arabian Peninsula, E28 1 patient of Turkish descent E29 and 4 patients from 2 different Qatari families E30 have been reported.IKK-related genetic diseases have been reviewed. E31

Three (3) of the patients reported by Pannicke et al (2013) E27 received HCT, and 2 survived with improvement of their clinical condition.

HCT appears promising.

CTPS-1 AR LOF (Cytidine 5’ Triphosphate Synthetase-1)

Mutation:CTPS1

References:Martin et al (2014)E32

This mutation is a defect of the pyrimidine pathway. Activated T-cells and B-cells have decreased levels of CTP and impaired proliferative responses to antigen receptor-mediated activation. Patients experience early onset severe chronic viral infections mostly caused by herpes viruses.

Eight (8) children from 5 families in northwest England have been reported. E32

Of 6 who received HCT, 4 survived, with improvement in their clinical condition E32.

Allogeneic HCT appears promising.

Immunoglobulin Class Switch Recombination Deficiencies (CD40 Ligand Deficiency / X-Linked Hyper IgM Syndrome; HIGM)

Mutation:CD40 Ligand (CD40LG, also called TNFRSF5)

References:Johnson et al (2007, update 2013),E33

Qamar et al (2014),E34

Thomas et al (1995),E35

Gennery et al (2004)E36

Immunoglobulin isotype switching is impaired due to defects in the CD40 ligand / CD40 signaling pathway. X-linked forms are due to defects in the CD40 ligand gene or NF-kB essential modulator; AR forms are due to defects in CD40 or downstream signaling molecules.E34

The prevalence of the disease has been reviewed. E33,E34

The first case report of HCT for CD40LG deficiencywas reported in 1995.E35 European experience of 38 cases from 8 countries has been reported, E36 and there are several subsequent reports.Collaborative efforts to summarize the retrospective HCT experience are underway: IEWP-EBMT & PIDTC; and Morena et al (unpublished).

Allogeneic HCT is curative if performed prior to onset of life-threatening complications of disease.

36

MHC Class II Deficiency AR LOF (Bare Lymphocyte Syndrome, Type II)

Mutations:Transcription factors for MHC Class II proteins: CIITA, RFX5, RFXAP; RFXANK

References:Hanna et al (2014),E37

Saleem et al (2000),E38

Ouederni et al (2011)E39

HLA Class II gene expression is lacking, with absence of T-cell and B-cell immune response to foreign antigens, and impaired antibody production. The genetic basis is the result of mutations in genes coding for transcription factors that normally regulate the expression of the MHC II genes (CIITA and subunits of RFX). Patients usually present with clinical findings of CID, and experience extreme susceptibility to viral, bacterial and fungal infections. MHC Class II deficiency may account for about 5% of typical SCID.

About 200 patients have been reported worldwide, the majority of North African origin.E37 Reports include 10 children from 8 kindreds E38 and 35 patients from 30 kindreds.E39

Six of the patients reported by Saleem et al(2000)E38 received HCT and 2 survived; 23 of the patients reported by Ouederni et al(2011)E39 received HCT and 10 were cured with recovery of almost normal immune functions.

HCT is currently the only curative treatment, and is considered the treatment of choice;E39

transplant at a young age is recommended.

PI3K Delta GOF (Phosphaditylinositol-3-OH Kinase Delta Catalytic Subunit) (Activated PI3K Delta Syndrome; APDS)

Mutation:PIK3CD

References:Angulo et al (2013)E40

Hartman et al (2015)E41

Defects in T-cell function with deficiency of naive T cells and an excess of senescent effector T cells. Defects in B-cell function with increased IgM, reduced IgG2, and impaired vaccine responses. Patients experience recurrent sinopulmonary infections, progressive airway damage, CMV and EBV viremia and lymphoproliferation.

Seven unrelated families with 17 affected individualsE40 and a single family with 5 affected individuals E41 have been described.

HCT has been used in 1 patient successfully, but long-term data regarding efficacy is not yet available. E41

HCT may be effective.

ZAP-70 (Zeta Chain (TCR) Associated Protein Kinase 70)

Mutation:ZAP70

References:Karaca et al (2013),E42

Fischer et al (2010),E43

Barata et al (2001),E44

Fagioli et al (2003)E45

ZAP-70 is a tyrosine kinase associated with the zeta chain of the TCR, and undergoes phosphorylation upon TCR activation. Deficiency leads to abnormal thymic development and abnormal T-cells in the periphery, including absence of CD8+ T-cells and anergic CD4+ T-cells unresponsive to mitogens. Patients have failure to thrive and early onset of severe life-threatening infections.

Karaca et al(2013)E42 have summarized reports of 12 cases with ZAP-70 mutations leading to SCID and related phenotypes. In total, about 20 patients from different families have been described. E43

Allogeneic HCT has been successfully used in several cases.E43 One such case E44 and an additional caseE45 have been reported.

HCT is the only curative treatment available.

Predominantly Antibody DeficienciesCommon Variable Immunodeficiency (CVID) (Hypoglobulinemia with Normal / Low Number of B Cells)

Mutations:Various; heterogeneous

References:Wehr et al (2015)E46

CVID is immunologically and genetically heterogeneous, with hypogammaglobulinemia of at least 2 immunoglobulin isotypes. The severity of disease may correlate with aspects of T-cell deficiency. Patients experiencing only infections may have normal life expectancy; in contrast, those with comorbidities including splenomegaly, granuloma, autoimmunity, enteropathy, liver disease, interstitial lung disease or

Incidence of CVID is high among the PID, between 1:10,000 and 1: 50,000.

Wehr et al E46 have studied outcomes of HCT for 25 patients with CVID.

HCT can be curative, and investigation as therapy for a subgroup of patients with CVID having complicated course with high mortality is warranted.

37

neoplasia have compromised life expectancy.

Phagocyte DefectsGATA 2 Deficiency (MonoMAC Syndrome)

Mutation:GATA2

References:Hsu et al (2015),E47

Grossman et al (2014),E48

Cuellar-Rodriguez et al (2011)E49

GATA-2 is a zinc finger hematopoietic transcription factor critical for embryonic and definitive hematopoiesis, and for lymphatic angiogenesis. Heterozygous mutations appear to cause haploinsufficiency due to either protein dysfunction or uniallelic reduced transcription.E47 Severely deficient monocyte, B-cell and NK-cell populations are present. Patients have various phenotypes including viral and bacterial infections, cytopenias, myelodysplasia, myeloid leukemias, pulmonary alveolar proteinosis and lymphedema.E47

GATA-2 has now been reported as the cause of many diverse phenotypes, which suggests that additional phenotypes may emerge. E47

Of 14 patients who received HCT, 8 are alive with reconstitution of deficient cellular populations and reversal of the clinical phenotype at median follow-up of 3.5 years; 2 patients rejected the graft and 1 relapsed with MDS after transplantation.E48

Of 6 additonal patients, E49 5 had corrected monocyte, B-cell and NK-cell counts with improvement of the clinical phenotype at median follow-up of 17.4 months.

The underlying defect is bone marrow dysfunction. HCT has been successful for both hemato-poietic and pulmonary alveolar proteinosis repair.

Genetic Disorders of Immune RegulationCTLA4 / CD152 (Cytotoxic T Lymphocyte Antigen-4) Haplo-insufficiency

Mutation:CTLA4

References:Schubert et al (2014),E50

Kuehn et al (2014)E51

Haploinsufficiency of human CTLA-4 causes dysregulation of FoxP3+ regulatory T-cells, hyperactivation of effector T cells, and lymphocytic infiltration of target organs.E51 Patients have an immune dysregulation syndrome with hypogammaglobulinemia, recurrent infections and multiple autoimmune clinical features.E50

Heterozygous mutations from 6, E50 and from 4 E51 unrelated families have been identified.

One (1) patient was transplanted over 1 year ago (personal communication), and is currently surviving. The patient has 100% donor chimerism and is clinically improved at last follow up.

HCT appears promising.

LRBA Deficiency (Lipopolysaccharide-Responsive Beige-Like Anchor Protein)

Mutation:LRBA

References:Lopez-Herrera et al (2012),E52

Seidel et al (2015)E53

Patients have hypogammaglobulinemia, infections and autoimmunity, such as inflammatory bowel disease and autoimmune cytopenias.

Homozygous mutations have been identified in 4 families, E52 and in 1 family. E53

One (1) patient is reported to have received HCT;E53 1 additional patient has also been transplanted (personal communication). Both are currently surviving and have 100% donor chimerism. However the first patient E53 subsequently developed ITP refractory to

HCT may have promise; further investigation is needed.

38

therapy, and the second also continues to have complications.

Familial HLH (FHL-1 through FHL-5; Includes Perforin, Munc 13-4, Syntaxin 11, and Munc 18-2 Defects)

Mutations:Include: PFR1, UNC13D, STX11, STXBP2 (UNC18B)

References:Janka et al (2013),E54

Zhang et al (2011),E55

Horne et al (2005),E56

Ouachee-Chardin et al (2006),E57

Marsh et al (2010)E58

Genes and proteins affected are described in Table 1 of Janka et al (2013).E54 All of the FHL genes are involved in cytotoxic granule exocytosis or function. HLH is a hyperinflammatory syndrome caused by excessive activation of lymphocytes and macrophages with high levels of cytokines; symptoms include cytopenias; HLH has high mortality even with appropriate treatment.

Among 175 adult patients with HLH, hypomorphic monoallelic or biallelic mutations in FHL genes were found in 14%.E55

HCT for 86 cases of HLH (including 29 FHL cases) has been described.E56

Outcomes of HCT for an additional 48 cases of FHL have been examined. E57 Remission of HLH prior to HCT is desirable.

In patients with genetic HLH, HCT is curative for the immune defect. RIC may be preferred due to increased mortality with MAC regimens.E58

HLH and XLP Associated with Immunodeficiency Syndromes (XLP-1, XLP-2; Includes SAP and XIAP Defects)

Mutations:Include: LYST, RAB27A, SH2D1A, BIRC4

References:Janka et al (2013),E54

Booth et al (2011)E59

Marsh et al (2014),E60

Genes and proteins affected are described in Table 1 of Janka (2013).E54 Processing of cytotoxic vesicles is impaired. XLP-1 is commonly characterized by fulminant EBV infection and/or HLH after EBV infection, B-cell lymphoma, and other complications.

XLP-1 is rare among PID; management and outcome have been described. E59

HCT is often performed to improve long term survival. Outcomes of HCT have been described for 43 patients with XLP-1.E59 Use of RIC for 16 patients with XLP-1 from a single center, with 80% 1-year OS, and 71% long-term survival, has been described.E60

For XLP-1, HCT has been shown to have benefit, and is associated with resolution of HLH and lymphoma.E60 HCT for XLP-2 should be based on the severity of the clinical course.

Autoimmune Lymphoproliferative Syndrome (ALPS)

Mutation:FAS (two-thirds of patients); and undefined

References:Shah et al (2014),E61

Bleesing et al (2006, update 2014),E62

Dimopoulou et al (2007),E63

Sleight et al (1998),E64

Benkerrou et al (1997)E65

Germline defects of FAS are the most commonly identified abnormality in ALPS.E61,E62 ALPS is characterized by immune dysregulation due to inability to regulate lymphocyte homeostasis through abnormalities in apoptosis. Expansion of T-cells that have the alpha/beta TCR, but lack both CD4 and CD8, and defective FAS-mediated apoptosis in vitro is typical. Patients have lymphoproliferative and autoimmune diseases.

Prevalence of ALPS is unknown. A distinction needs to be made between presence of the cellular phenotype (defective FAS-mediated apoptosis) and penetrance of the clinical phenotype (ALPS). Factors determining penetrance of clinical ALPS are not presently understood.E62

Experience with HCT for ALPS is limited; case reports demonstrating correction of the clinical phenotype for 3 patients have been published.E63-E65

HCT may be indicated for those with severe clinical phenotypes (ALPS-FAS), severe and/or refractory cytopenias, or lymphoma. RIC regimens may be a realistic option for patients with comorbidities due to the disease.

Immuno-dysregulation, IPEX is due to germline Extremely rare; no At least 28 HCT is needed

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Polyendocrinopathy, Enteropathy, X-Linked (IPEX)

Mutation:FOXP3

References:D’Hennezel et al (2012),E66

Barzaghi et al (2012),E67

Horino et al (2014),E68

Burroughs et al (2007),E69

Burroughs et al (2010)E70

mutations in the FOXP3 gene, a master transcriptional regulator for development of CD4 regulatory T-cells (Treg). Patients experience severe, multi-organ autoimmune phenomena including enteropathy, chronic dermatitis, endocrinopathy, hepatitis, nephritis and cytopenias.E66,E67 Patients do not survive long-term without BMT.

estimates of incidence have been proposed.

patients have received HCT for IPEX; 6 died of disease or during conditioning; 15 of these are summarized in Table 5 of Barzaghi et al (2012).E67 At least 2 additional cases have been reported.E68,E69

for correction of the immune defect. Early HCT leads to the best outcome. RIC may be pre-ferred.E69,E70

Defects in Innate Immunity; Receptors & Signaling ComponentsNF Kappa B Essential Modulator (NEMO)

Mutation:NEMO (IKBKG)

References:Orange et al (2004),E71

Braue et al (2015),E72

Nishikomori (2004)E73

Mutations in the nuclear factor-κB essential modulator (NEMO) gene, a member of the nuclear factor kB (NF-kB) pathway, impair NF-kB function, and generally induce broad susceptibility to bacteria, viruses, and fungi. Immunologic findings include hypogammaglobulinemia and decreased NK cytotoxic activity. Serious bacterial illness early in life and later mycobacterial disease are typical. Clinical features may include ectodermal dysplasia and incontinentia pigmenti.

Orange et al (2004)E71 estimate incidence to be 1:250,000 live male births. Seven pateints,E71 1 patientE72 and 1 patientE73 have been described.

At least 1 patient with NEMO has undergone successful HCT (personal communication reported in Orange et al (2004) E71).

Due to limited experience, comment on HCT is likely premature.

Complement DeficienciesC1q Deficiency

Mutation:C1QA

References:Kouser et l (2015),E74

van Schaarenburg et al (2015),E75

Arkwright et al (2014)E76

Complement protein C1q is the recognition molecule of the classical pathway, and performs a diverse range of complement and non-complement functions. Ligands derived from self, non-self, and altered self are bound, and it can modulate the functions of immune and non-immune cells including dendritic cells and microglia.E74 C1q may be involved in the clearance of apoptotic cells and subsequent B cell tolerance.E74 Patients with C1q deficiency may have lupus and infections, and appear to have reduced survival.

Globally, about 60 cases of C1q deficiency have been published.E75 In a report of 45 patients from 31 families, 36 (80%) suffered from SLE of which 16 (36%) had SLE and infections, 5 (11%) had infections only and 4 (9%) had no symptoms.E75

HCT has been attempted in 3 C1q deficient patients, with improvement of clinical symptoms and restoration of C1q production.E75,E76

HCT may be clinically beneficial.

Other Well-Defined Immuno-deficiencies

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ADA-2 (Deficiency of Adenosine Deaminase-2); CECR1 LOF (Cat Eye Syndrome Chromosome Region, Candidate 1)

Mutation:CECR1

References:Zhou et al (2014),E77

Navon Elkan et al (2014),E78

Van Montfrans et al (2014),E79

Van Eyck et al (2014)E80

LOF mutations in CECR1 are associated with vascular and inflammatory changes.E77,E78 Patients experience intermittent fevers, early onset stroke and vasculopathy.

Nine (9) patients are described.E77

Two HCT procedures reported, both patients are surviving as of July 2015.E79,E80

For both patients, vasculopathy appears to have resolved following HCT.

PGM3 deficiency (phospho-glucomutase 3) AR Hypomorphic Mutations

Mutation:PGM3

References:Stray-Pedersen et al (2014),E81

Zhang et al (2014)E82

Sassi et al (2014),E83

PGM-3 affects multiple glycosylation pathways; PGM-3 deficiency is an AR genetic syndrome of severe atopy, increased serum IgE levels, immune deficiency, autoimmunity, and motor and neurocognitive impairment. (Hyper IgE syndrome (HIES) with neurological impairment). The immunologic mechanism of the link between glycosylation abnormalities and immune dysregulation is not yet understood.

Three (3) patients from 3 families,E81 and 8 patients from 2 families,E82 and 9 patients from 2 families in TunisiaE83 have been reported.

HCT procedures resulted in correction of neutropenia and lymphopenia in 2 patients.E81

HCT appears promising.

Cartilage Hair Hypoplasia (CHH) (McKusick Type Metaphyseal Chondrodysplasia)

Mutation:RMRP

References:Kavadas et al (2008)E84

Mäkitie et al (1993),E85

CHH is a highly pleiotropic AR disorder caused by mutations in the ribonuclease mitochondrial RNA processing (RMRP) gene, and characterized by short-limbed dwarfism due to skeletal dysplasia; some patients may be predisposed to malignancies. Immunologic findings are variable, and may include CID, decreased T-cells with CD8 lymphopenia, and decreased mitogenic responses.E84 Mortality from infections early in childhood may occur.

A study of 108 Finnish patients with CHH has been published.E85 Immunologic features of 12 patients have been described.E84

HCT has been described for 6 patients, all of whom survived at a median of 7 years post-transplant, with clinical and immunologic improvement.E84 Indications for HCT included Omenn syndrome (4 patients) and CID (2 patients).

HCT may be indicated for the immunologic complications of CHH.

Dyskeratosis Congenita (DKC); X-linked DKC1; AD TERC, TERT, or TINF2; AR NOP10, NHP2, or TCAB1

Mutations:DKC1 accounts for 40% of cases; TERT, TERC, TINF2, NOP10, NHP2, TCAB1 and

DKC is a disorder of poor telomere maintenance, due to a number of gene mutations that lead to impaired ribosomal function.E86 Phenotypically patients have a triad of abnormal skin pigmentation, nail dystrophy and leukoplakia of the oral mucosa. About 90% have peripheral cytopenia of one or more lineages, and at least

Estimated annual incidence is less than 1:1,000,000.E87

HCT outcomes have been described for 34 patients.E88 Survival was 30%, 14 patients were alive at last follow-up. Transplantation from MSD using cyclo-phosphamide

Allogeneic HCT is the only curative treatment for the associated bone marrow failure.

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CI6orf57 account for 20% of cases; 40% are unidentified

References:Townsley et al (2014)E86

Fernandez Garcia et al (2014),E87

Gadalla et al (2013),E88

70% of deaths are related to bleeding and opportunistic infections resulting from bone marrow failure.

non-radiation containing regimens was associated with low early toxicity. Pulmonary complications and underlying disease contributed to late mortality.

Abbreviations: AD, autosomal dominant; AR, autosomal recessive; BCG, Bacille Calmette-Guerin; CID, combined immunodeficiency; CLL, chronic lymphocytic leukemia; CVID, common variable immune deficiency; GOF, gain of function; HLH, hemophagocytic lymphohistiocytosis; LOF, loss of function; MAC, myeloablative conditioning; MDS, myelodysplastic syndrome; MHC, major histocompatibility complex; NFkB, nuclear factor kB; NK, natural killer; OS, overall survival; PD, partial dominant; PjP, Pneumocystis jivrovecii pneumonia; RIC, reduced intensity conditioning; WT, wild type, XLP, X-linked lymphoproliferative syndrome.

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