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1 2 ELECTRONIC SUPPLEMENT 3 4 5 APPENDIX E1 6 7 PIDTC LEADERSHIP WORKSHOP, BETHESDA, MD, APRIL 19-20, 2015 8 9 Steering Committee 10 11 Morton J. Cowan, MD, Division of Allergy/Immunology and Blood and Marrow 12 Transplantation, Department of Pediatrics and UCSF Benioff Children’s Hospital, University of 13 California San Francisco, San Francisco, CA 14 15 Linda M. Griffith, MD, MHS, PhD, Division of Allergy, Immunology and Transplantation, 16 National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 17 MD 18 19 Donald B. Kohn, MD, Departments of Microbiology, Immunology & Molecular Genetics and 20 Pediatrics, University of California Los Angeles, Los Angeles, CA 21 22 Luigi D. Notarangelo, MD, Division of Immunology, Children’s Hospital, and Harvard Stem 23 Cell Institute, Harvard Medical School, Boston, MA 24 25 Jennifer M. Puck, MD, Institute for Human Genetics, and Division of Allergy/Immunology and 26 Blood and Marrow Transplantation, Department of Pediatrics and UCSF Benioff Children’s 27 Hospital, University of California San Francisco, San Francisco, CA 28 29 Additional Discussants 30 31 Marcia Boyle, Immune Deficiency Foundation, Towson, MD 32 33 Rebecca H. Buckley, MD, Pediatric Allergy and Immunology, Duke University School of 34 Medicine, Durham, NC 35 36 Lauri M. Burroughs, MD, Pediatric Hematology/Oncology, Fred Hutchinson Cancer Research 37 Center, University of Washington School of Medicine, Seattle, WA 38 39 Elizabeth Dunn, MA, Pediatric Allergy/Immunology and Blood and Marrow Transplant 40 Division, UCSF Benioff Children’s Hospital, University of California, San Francisco, CA 41 42 Christopher C. Dvorak, MD, Pediatric Allergy/Immunology and Blood and Marrow Transplant 43 Division, UCSF Benioff Children’s Hospital, University of California, San Francisco, CA 44 45 Thomas A. Fleisher, MD, Department of Laboratory Medicine, Clinical Center, National 46 Institutes of Health, Bethesda, MD 47

1 48 Elie Haddad, MD, PhD, Pediatric Immunology and Pediatrics, Mother and Child Ste-Justine 49 Hospital, University of Montreal, Montreal, QC, Canada 50 51 Elizabeth M. Kang, MD, Laboratory of Host Defenses, National Institute of Allergy and 52 Infectious Diseases, National Institutes of Health, Bethesda, MD 53 54 Brent R. Logan, PhD, Center for International Blood and Marrow Transplant Research and 55 Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI 56 57 Harry L. Malech, MD, Laboratory of Host Defenses, National Institute of Allergy and 58 Infectious Diseases, National Institutes of Health, Bethesda, MD 59 60 James G. McNamara, MD, Division of Allergy, Immunology and Transplantation, National 61 Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 62 63 Richard J. O'Reilly, MD, Pediatrics and Immunology, Memorial Sloan Kettering Cancer 64 Center, New York, NY 65 66 Sung-Yun Pai, MD, Pediatric Hematology/Oncology, Children’s Hospital, Harvard Medical 67 School, Boston, MA 68 69 Robertson Parkman, MD, Blood and Marrow Transplantation, Lucille Packard Children’s 70 Hospital, Stanford University School of Medicine, Stanford, CA 71 72 Michael A. Pulsipher, MD, Children’s Center for Cancer and Blood Diseases, Pediatric 73 Hematology/Oncology, Children’s Hospital Los Angeles, Keck School of Medicine, University 74 of Southern California, Los Angeles, CA 75 76 William T. Shearer, MD, PhD, Pediatric Allergy & Immunology, Texas Children's Hospital, 77 Baylor College of Medicine, Houston TX 78 79 80

81

2 82 APPENDIX E2

83 PIDTC ANNUAL SCIENTIFIC WORKSHOPS - HOUSTON, TX, MAY 2-4, 2013 84 (THIRD); SEATTLE, WA, MAY 1-3, 2014 (FOURTH); AND MONTREAL, QUEBEC, 85 CANADA, APRIL 30 - MAY 2, 2015 (FIFTH), WITH EDUCATION DAY, APRIL 29-30, 86 2015 87 88 Workshop Co-Chairs and Local Organizing Committees 89 90 Lauri M. Burroughs, MD, Pediatric Hematology/Oncology, Fred Hutchinson Cancer Research 91 Center, University of Washington School of Medicine, Seattle, WA (Seattle, WA, 2014) 92 93 Morton J. Cowan, MD, Division of Allergy/Immunology and Blood and Marrow 94 Transplantation, Department of Pediatrics and UCSF Benioff Children’s Hospital, University of 95 California San Francisco, San Francisco, CA 96 97 Hélène Decaluwe, MD, PhD, Pediatric Immunology and Pediatrics, Mother and Child Ste- 98 Justine Hospital, University of Montreal, Montreal, QC, Canada (Montreal, Canada, 2015) 99 100 Linda M. Griffith, MD, MHS, PhD, Division of Allergy, Immunology and Transplantation, 101 National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 102 MD 103 104 Elie Haddad, MD, PhD, Pediatric Immunology and Pediatrics, Mother and Child Ste-Justine 105 Hospital, University of Montreal, Montreal, QC, Canada (Montreal, Canada, 2015) 106 107 Donald B. Kohn, MD, Departments of Microbiology, Immunology & Molecular Genetics and 108 Pediatrics, University of California Los Angeles, Los Angeles, CA 109 110 Luigi D. Notarangelo, MD, Division of Immunology, Children’s Hospital, and Harvard Stem 111 Cell Institute, Harvard Medical School, Boston, MA 112 113 Jennifer M. Puck, MD, Institute for Human Genetics, and Division of Allergy/Immunology and 114 Blood and Marrow Transplantation, Department of Pediatrics and UCSF Benioff Children’s 115 Hospital, University of California San Francisco, San Francisco, CA 116 117 William T. Shearer, MD, PhD, Pediatric Allergy & Immunology, Texas Children's Hospital, 118 Baylor College of Medicine, Houston TX (Houston, TX, 2013) 119 120 Troy R. Torgerson, MD, PhD, Pediatric Rheumatology, Seattle Children’s Research Institute, 121 University of Washington School of Medicine, Seattle, WA (Seattle, WA, 2014) 122 123 Invited Speakers 124 125 Roshini S. Abraham, PhD, Department of Laboratory Medicine and Pathology, Mayo College 126 of Medicine, Rochester, MN

3 127 128 Michael H. Albert, MD, Department of Hematology and Oncology, Munich Children’s 129 Hospital, Munich, Germany 130 131 Barbara Ballard, Immune Deficiency Foundation, Towson, MD 132 133 Carmem Bonfim, MD, Bone Marrow Transplantation Center, Federal University of Parana, 134 Curitiba, Brazil 135 136 Marcia Boyle, Immune Deficiency Foundation, Towson, MD 137 138 Malcolm K. Brenner, MD, PhD, Center for Cell and Gene Therapy, Baylor College of 139 Medicine, Texas Children’s Hospital, Houston, TX 140 141 Amy Brower, PhD, Newborn Screening Translational Research Network, American College of 142 Medical Genetics and Genomics, Bethesda, MD 143 144 Rebecca H. Buckley, MD, Pediatric Allergy and Immunology, Duke University School of 145 Medicine, Durham, NC 146 147 Frederick D. Bushman, PhD, Department of Microbiology, Perelman School of Medicine, 148 University of Pennsylvania, Philadelphia, PA 149 150 Jayanta Chaudhuri, PhD, Immunology Program, Memorial Sloan-Kettering Cancer Center, 151 New York, NY 152 153 Charlotte Cunningham-Rundles, MD, PhD, Pediatric Clinical Immunology, Mount Sinai 154 School of Medicine, New York, NY 155 156 Carole Ann Demaret, The David Center, Texas Children’s Hospital, Houston, TX 157 158 Morna J. Dorsey, MD, MMSc, Pediatric Immunology and Allergy Center, Department of 159 Pediatrics and UCSF Benioff Children’s Hospital, University of California San Francisco, San 160 Francisco, CA 161 162 Christopher C. Dvorak, MD, Pediatric Allergy/Immunology and Blood and Marrow Transplant 163 Division, UCSF Benioff Children’s Hospital, University of California, San Francisco, CA 164 165 Alain Fischer, MD, PhD, National Health Institute of Medical Research (INSERM) and 166 Department of Pediatric Immunology, Necker Hospital, Paris France 167 168 Thomas A. Fleisher, MD, Department of Laboratory Medicine, Clinical Center, National 169 Institutes of Health, Bethesda, MD 170 171 Danielle N. Friedman, MD, Pediatric Long-Term Follow-Up Program, Memorial Sloan- 172 Kettering Cancer Center, New York, NY

4 173 174 Ephraim J. Fuchs, MD, Department of Hematology and Oncology, Johns Hopkins University 175 School of Medicine, Baltimore, MD 176 177 Andrew R. Gennery, MD, Institute of Cellular Medicine, Great North Children’s Hospital, 178 Newcastle University, Newcastle upon Tyne, UK 179 180 Georg A. Hollander, MD, Department of Biomedicine, University of Basel, Switzerland 181 182 Emily Hovermale, Immune Deficiency Foundation, Towson, MD 183 184 Alan Hurley, Chronic Granulomatous Disease Association, San Marino, CA 185 186 Mary Hurley, Chronic Granulomatous Disease Association, San Marino, CA 187 188 Kohsuke Imai, MD, PhD, Department of Pediatrics, Tokyo Medical and Dental University, 189 Tokyo, Japan 190 191 Sumathi Iyengar, MD, Wiskott-Aldrich Foundation, Inc., Smyrna, GA 192 193 Elizabeth M. Kang, MD, Laboratory of Host Defenses, National Institute of Allergy and 194 Infectious Diseases, National Institutes of Health, Bethesda, MD 195 196 Jeffrey Krischer, PhD, Division of Bioinformatics and Biostatistics, Department of Pediatrics, 197 University of South Florida College of Medicine, Tampa, FL 198 199 Franco Locatelli, MD, PhD, Pediatric Hematology/Oncology and Transfusion Medicine, 200 Bambino Gesu Children’s Hospital, Rome, Italy 201 202 Brent R. Logan, PhD, Center for International Blood and Marrow Transplant Research and 203 Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI 204 205 James R. Lupski, MD, PhD, Department of Molecular and Human Genetics, Baylor College of 206 Medicine, Houston, TX 207 208 Harry L. Malech, MD, Laboratory of Host Defenses, National Institute of Allergy and 209 Infectious Diseases, National Institutes of Health, Bethesda, MD 210 211 M. Louise Markert, MD, PhD, Pediatric Division of Allergy and Immunology, Duke 212 University School of Medicine, Durham, NC 213 214 Fred Modell, Jeffrey Modell Foundation, New York, NY 215 216 Vicki Modell, Jeffrey Modell Foundation, New York, NY 217

5 218 Hans Ochs, DM, Center for Immunity and Immunotherapy, Seattle Children’s Hospital 219 Research Institute, University of Washington School of Medicine, Seattle, WA 220 221 Jordan S. Orange, MD, PhD Immunology, Allergy and Rheumatology, Texas Children’s 222 Hospital, Baylor College of Medicine, Houston, TX 223 224 Richard J. O'Reilly, MD, Pediatrics and Immunology, Memorial Sloan Kettering Cancer 225 Center, New York, NY 226 227 Sung-Yun Pai, MD, Pediatric Hematology/Oncology, Children’s Hospital, Harvard Medical 228 School, Boston, MA 229 230 Elena E. Perez, MD, PhD, Pediatric Allergy and Immunology, Batchelor Research Institute, 231 University of Miami School of Medicine, Miami, FL 232 233 Claude Perreault, MD, Institute for Research in Immunology and Cancer (IRIC), University of 234 Montreal, Canada 235 236 Matthew H. Porteus, MD, PhD, Pediatric Hematology/Oncology, Lucile Packard Children’s 237 Hospital, Stanford University School of Medicine, Stanford, CA 238 239 Michael A. Pulsipher, MD, Children’s Center for Cancer and Blood Diseases, Pediatric 240 Hematology/Oncology, Children’s Hospital Los Angeles, Keck School of Medicine, University 241 of Southern California, Los Angeles, CA 242 243 David J. Rawlings, MD, Pediatric Immunology, Seattle Children’s Research Institute, 244 University of Washington School of Medicine, Seattle, WA 245 246 Maria-Grazia Roncarolo, MD, Division of Pediatric Translational and Regenerative Medicine, 247 Institute for Stem Cell Biology and Regenerative Medicine, Lucille Packard Children’s Hospital, 248 Stanford University School of Medicine, Stanford, CA 249 250 Christopher Scalchunes, Immune Deficiency Foundation, Towson, MD 251 252 Judith Shizuru, MD, PhD, Division of Blood and Marrow Transplantation, Department of 253 Medicine, Stanford University School of Medicine, Stanford, CA 254 255 Heather Smith, SCID Angels for Life Foundation, Lakeland, FL 256 257 Robert Sokolic, MD, Office of Cell Tissue and Gene Therapies, CBER, FDA, Silver Spring, 258 MD 259 260 Ricardo Sorensen, MD, Department of Pediatrics, Children’s Hospital, LSU School of 261 Medicine, New Orleans, LA 262

6 263 Paul Szabolcs, MD, Bone Marrow Transplantation and Cellular Therapies, Children’s Hospital 264 of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA 265 266 Claudia Wehr, MD, Center for Chronic Immunodeficiency, University Medical Center Freiburg 267 and the University of Freiburg, Freiburg, Germany 268 269 Irving Weissman, MD, Institute for Stem Cell Biology and Regenerative Medicine, Stanford 270 University School of Medicine, Stanford, CA 271 272 Additional Discussants 273 274 Jordan Abbott, MA, MD, Pediatric Allergy and Clinical Immunology, National Jewish Health, 275 Denver, CO 276 277 Rolla F. Abu-Arja, MD, Pediatric Hematology/Oncology, Nationwide Children’s Hospital, 278 Columbus, OH 279 280 Stephanie Albin, MD, Pediatrics, Children’s Hospital of Philadelphia, Perelman School of 281 Medicine, University of Pennsylvania, Philadelphia, PA 282 283 Doerthe Adriana Andreae, MD, Pediatrics, Mount Sinai Hospital, New York, NY 284 285 Victor Aquino, MD, Pediatric Hematology-Oncology, University of Texas Southwestern, 286 Dallas, TX 287 288 Rosa Bachetta, MD, Division of Pediatric Translational and Regenerative Medicine, Institute 289 for Stem Cell Biology and Regenerative Medicine, Lucille Packard Children’s Hospital, Stanford 290 University School of Medicine, Stanford, CA 291 292 K. Scott Baker, MD, MS, Fred Hutchinson Cancer Research Center Survivorship Program, and 293 Pediatric Blood and Marrow Transplant, Seattle Children’s Hospital and University of 294 Washington, Seattle, WA 295 296 Bezhad B. Bidadi, MD, Pediatric Hematology/Oncology, Mayo Clinic, Rochester, MN 297 298 Henrique Bittencourt, MD, Pediatric Hematology/Oncology, Mother and Child Ste-Justine 299 Hospital, Montreal, Quebec, Canada 300 301 Jeffrey J. Bednarski, MD, PhD, Pediatric Hematology/Oncology, St. Louis Children’s 302 Hospital, Washington University School of Medicine, St. Louis, MO 303 304 Jack J. H. Bleesing, MD, PhD, Department of Pediatrics, Cincinnati Children’s Hospital 305 Medical Center, Cincinnati,OH 306 307 Richard J. Bram, MD, PhD, Pediatric Immunology, Mayo Clinic, Rochester, MN 308

7 309 Nancy J. Bunin, MD, Pediatric Hematology/Oncology, Children’s Hospital of Philadelphia, 310 Philadelphia, PA 311 312 Jessica Carlson, Pediatric Allergy/Immunology and Blood and Marrow Transplant Division, 313 UCSF Benioff Children’s Hospital, University of California, San Francisco, CA 314 315 Sonia Cellot, MD, Institute for Research in Immunology and Cancer (IRIC), University of 316 Montreal, Canada 317 318 Alice Chan, MD, Pediatric Allergy/Immunology and Rheumatology, UCSF Benioff Children’s 319 Hospital, University of California San Francisco, CA 320 321 Ka Wah Chan, MD, Pediatric Blood and Marrow Transplant, Methodist Hospital/Texas 322 Transplant Institute, University of Texas Health Science Center, San Antonio, TX 323 324 Joseph H. Chewning II, MD, Pediatric Hematology/Oncology, University of Alabama, 325 Birmingham, AL 326 327 Hey Jin Chong, MD, PhD, Pediatric Allergy and Immunology, Children’s Hospital of 328 Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA 329 330 Julia I. Chu, MD, Pediatric Hematology/Oncology, Boston Children’s Hospital, Harvard 331 Medical School, Boston, MA 332 333 James Albert Connelly, MD, Pediatric Hematology/Oncology, C. S. Mott Children’s Hospital, 334 University of Michigan, Ann Arbor, MI 335 336 Guilhem Cros, MD, Pediatric Immunology and Pediatrics, Mother and Child Ste Justine 337 Hospital, University of Montreal, Montreal, QC, Canada 338 339 Geoff Cuvelier, MD, Pediatric Hematology/Oncology, University of Manitoba, Manitoba, 340 Canada 341 342 Blachy Davila-Saldana, MD, Pediatric Hematology/Oncology, Cincinnati Children’s Hospital 343 Medical Center, Cincinnati, OH 344 345 Jean-Jacques De Bruycker, MD, Pediatric Immunology and Pediatrics, Mother and Child Ste 346 Justine Hospital, University of Montreal, Montreal, QC, Canada 347 348 Yesim Demirdag, MD, Pediatric Allergy and Immunology, College of Physicians and Surgeons, 349 Columbia University Medical Center, New York, NY 350 351 Suk See De Ravin, MD, Laboratory of Host Defenses, National Institute of Allergy and 352 Infectious Diseases, National Institutes of Health, Bethesda, MD 353

8 354 Elizabeth Dunn, MA, Pediatric Allergy/Immunology and Blood and Marrow Transplant 355 Division, UCSF Benioff Children’s Hospital, University of California, San Francisco, CA 356 357 Michel Duval, MD, Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Centre, and 358 Pediatric Hematology / Oncology, Ste Justine Hospital, University of Montreal, Montreal, QC, 359 Canada 360 361 Alexandra H. Filipovich, MD, Pediatric Clinical Immunology, Division of Hematology / 362 Oncology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 363 364 Matthew Fletcher, MD, Pediatric Hematology/Oncology, Oschner Medical Center, New 365 Orleans, LA 366 367 Lisa R. Forbes, MD, Pediatric Allergy/Immunology, Children’s Hospital of Philadelphia, 368 Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 369 370 Ramsay L. Fuleihan, MD, Allergy/Immunology, Lurie Children’s Hospital of Chicago, 371 Northwestern University Feinberg School of Medicine, Chicago, IL 372 373 Erwin W. Gelfand, MD, Pediatric Allergy and Immunology, National Jewish Hospital, National 374 Jewish Health, Denver, CO 375 376 Alfred P. Gillio, MD, Pediatric Hematology/Oncology, Hackensack University Medical Center, 377 Hackensack, NJ 378 379 Frederick Goldman, MD, Blood and Marrow Transplant, and Pediatric Hematology/Oncology, 380 Children’s Hospital of Alabama, University of Alabama School of Medicine, Birmingham, AL 381 382 Eyal Grunebaum, MD, Pediatric Immunology/Allergy and Bone Marrow Transplantation, The 383 Hospital for Sick Children, University of Toronto, Ontario, Canada 384 385 Erin K. Ham, MD, Allergy and Immunology, Seattle Children’s Hospital, University of 386 Washington, Seattle, WA 387 388 Laura Hancock, Children’s Oncology Group Operations Center, Monrovia, CA 389 390 Imelda Celine Hanson, MD, Pediatric Allergy/Immunology, Baylor College of Medicine, 391 Texas Children’s Hospital, Houston, TX 392 393 Jennifer R. Heimall, MD, Pediatric Allergy/Immunology, Children’s Hospital of Philadelphia, 394 Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 395 396 Rosalie Helfrich, Division of Bioinformatics and Biostatistics, Department of Pediatrics, 397 University of South Florida College of Medicine, Tampa, FL 398

9 399 Avni Y. Joshi, MD, Pediatric Allergy-Immunology and Infectious Diseases, Mayo Clinic, 400 Rochester, MN 401 402 Neena Kapoor, MD, Division of Research Immunology/Blood and Marrow Transplant, 403 Children’s Hospital of Los Angeles, Keck School of Medicine, University of Southern 404 California, Los Angeles, CA 405 406 Michael D. Keller, MD, Pediatric Allergy and Immunology, Children’s National Medical 407 Center, Washington, DC 408 409 Shakila P. Khan, MD, Pediatric Blood and Marrow Transplantation, and 410 Hematology/Oncology, Mayo Clinic, Rochester, MN 411 412 Vy Kim, MD, Pediatric Allergy and Immunology, Hospital for Sick Children, University of 413 Toronto, Ontario, Canada 414 415 Morris Kletzel, MD, Pediatric Hematology/Oncology, Lurie Children’s Memorial Hospital, 416 Northwestern University School of Medicine, Chicago, IL 417 418 Alan P. Knutsen, MD, Pediatric Allergy/Immunology, Cardinal Glennon Children’s Hospital, 419 St. Louis University School of Medicine, St. Louis, MO 420 421 Z. Yesim Kucuk, MD, Pediatric Bone Marrow Transplantation and Immune Deficiency, 422 Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 423 424 Caroline Y. Kuo, MD, Pediatric Allergy and Immunology, University of California Los 425 Angeles, CA 426 427 Antonia Kwan, PhD, MRCPCH, Pediatrics, University of California San Francisco, CA 428 429 Jennifer W. Leiding, MD, Pediatric Allergy and Immunology, All Children’s Hospital, 430 University of South Florida, Tampa, FL 431 432 Lisa Lim, Seattle Cancer Care Alliance Network, Fred Hutchinson Cancer Research Center, 433 Seattle, WA 434 435 Janel R. Long-Boyle, PharmD, PhD, Department of Clinical Pharmacy, School of Pharmacy, 436 University of California, San Francisco, CA 437 438 Julia Lopes-Garcia, Pediatric Hematology / Oncology, Ste Justine Hospital, University of 439 Montreal, Montreal, QC, Canada 440 441 Reza Macaraeg, Seattle Cancer Care Alliance Network, Fred Hutchinson Cancer Research 442 Center, Seattle, WA 443 444 Paul J. Maglione, MD, PhD, Allergy and Immunology, Mount Sinai Hospital, New York, NY

10 445 446 Rebecca A. Marsh, MD, Pediatric Hematology/Oncology, Cincinnati Children’s Hospital, 447 Cincinnati, OH 448 449 Caridad Martinez, MD, Pediatric Hematology/Oncology, Texas Children’s Cancer Center, 450 Baylor College of Medicine, Houston, TX 451 452 Bhakti Mehta, MD, Pediatric Hematology/Oncology, Children’s Hospital of Los Angeles, Keck 453 School of Medicine, University of Southern California, Los Angeles, CA 454 455 Alexandra (Xanne) Miggelbrink, Boston Children’s Hospital, Harvard Medical School, 456 Boston, MA 457 458 Holly Miller, MD, Pediatric Hematology/Oncology, Mott Children’s Hospital, University of 459 Michigan, Ann Arbor, MI 460 461 Theodore B. Moore, MD, Pediatric Hematology/Oncology, UCLA Medical Center, University 462 of California, Los Angeles, CA 463 464 Maria Teresa de la Morena, MD, Pediatric Allergy/Immunology, Children’s Medical Center, 465 University of Texas Southwestern, Dallas, TX 466 467 Megan M. Morsheimer, MD, Pediatrics, UCSF Benioff Children’s Hospital, University of 468 California San Francisco, CA 469 470 Hana B. Niebur, MD, Pediatric Allergy and Immunology, All Children’s Hospital, University 471 of South Florida, Tampa, FL 472 473 Omar Niss, MD, Pediatric Hematology/Oncology, Cincinnati Children’s Hospital Medical 474 Center, Cincinnati, OH 475 476 Satiro de Oliveira, MD, Pediatric Hematology/Oncology, UCLA Medical Center, University of 477 California, Los Angeles, CA 478 479 Suhag H. Parikh, MD, Pediatric Blood and Marrow Transplantation, Duke University Medical 480 Center, Durham, NC 481 482 Kenneth Paris, MD, Pediatric Allergy/Immunology, Children’s Hospital of New Orleans, 483 Louisiana State University Health Sciences Center, New Orleans, LA 484 485 Robertson Parkman, MD, Blood and Marrow Transplantation, Lucille Packard Children’s 486 Hospital, Stanford University School of Medicine, Stanford, CA 487 488 Kiran P. Patel, MD, Pediatric Allergy and Immunology, UCSF Benioff Children’s Hospital, 489 University of California San Francisco, CA 490

11 491 Aleksandra Petrovic, MD, Pediatric Hematology/Oncology, All Children’s Hospital, St 492 Petersburg, FL 493 494 Susan Eliza Prockop, MD, Pediatric Hematology/Oncology, Memorial Sloan-Kettering Cancer 495 Center, New York, NY 496 497 Divya Punwani, MD, Pediatric Allergy and Immunology, UCSF Benioff Children’s Hospital, 498 University of California, San Francisco, CA 499 500 Troy C. Quigg, DO, MS, Pediatric Hematology/Oncology, Methodist Children’s Hospital, 501 Texas Transplant Institute, San Antonio, TX 502 503 Jo-Anne Richer, BSN, Pediatric Oncology, Mother and Child Ste-Justine Hospital, Montreal, 504 Quebec, Canada 505 506 Nicholas L. Rider, DO, Pediatric Allergy and Immunology, Texas Children’s Hospital, Baylor 507 College of Medicine, Houston, TX 508 509 John M. Routes, MD, Pediatric Allergy and Clinical Immunology, Children’s Hospital of 510 Wisconsin, Medical College of Wisconsin, Milwaukee, WI 511 512 Jacob Rozmus, MD, Pathology and Laboratory Medicine, BC Children’s Hospital, University 513 of British Columbia, Vancouver, BC, Canada 514 515 Holly Ruhlig, Data Management and Coordinating Center, Rare Diseases Clinical Research 516 Network, Division of Bioinformatics and Biostatistics, Department of Pediatrics, University of 517 South Florida College of Medicine, Tampa, FL 518 519 Blythe D. Sather, PhD, Department of Immunology, Seattle Children’s Hospital and University 520 of Washington, Seattle, WA 521 522 Marlis Schroeder, MD, Pediatric Hematology/Oncology, Faculty of Medicine, University of 523 Manitoba, Canada 524 525 Heather L. Schuback, MD, Pediatric Hematology/Oncology, Seattle Children’s Hospital and 526 University of Washington, Seattle, WA 527 528 Kirk R. Schultz, MD, Pediatric Hematology/Oncology and Transplantation, BC Children’s 529 Hospital, University of British Columbia, Vancouver, BC, Canada 530 531 Silvia Selleri, PhD, Department of Pediatrics, Mother and Child Ste-Justine Hospital, Montreal, 532 Quebec, Canada 533 534 Christine M. Seroogy, MD, Pediatric Allergy and Immunology, University of Wisconsin 535 Children’s Hospital, Madison, WI 536

12 537 Evan B. Shereck, MD, Pediatric Hematology/Oncology, Doernbecher Children’s Hospital, 538 Oregon Health & Science University, Portland, OR 539 540 Suzanne Skoda-Smith, MD, Pediatric Allergy/Immunology, Seattle Children’s Research 541 Institute, University of Washington School of Medicine, Seattle, WA 542 543 Trudy N. Small, MD, Pediatric Bone Marrow Transplant Service, Memorial Sloan Kettering 544 Cancer Center, New York, NY 545 546 Angela Smith, MD, MS, Pediatric Blood and Marrow Transplantation, University of Minnesota, 547 Minneapolis, MN 548 549 Bryce Corey Smithson, MD, Pediatrics, Children’s Hospital of Los Angeles, Keck School of 550 Medicine, University of Southern California, Los Angeles, CA 551 552 Heather Stefanski, MD, PhD, Pediatric Blood and Marrow Transplantation, University of 553 Minnesota, Minneapolis, MN 554 555 Mary Stoelinga, APN, NP, Pediatric Hematology/Oncology, Lurie Children’s Hospital, 556 Chicago, IL 557 558 Kathleen E. Sullivan, MD, PhD, Pediatric Immunology, Children’s Hospital of Philadelphia, 559 Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 560 561 Ho Yan Herman Tam, MD, Manitoba Institute of Child Health, Winnipeg, Canada 562 563 Agne Taraseviciute, MD, Pediatric Hematology/Oncology, Seattle Children’s Hospital and 564 University of Washington, Seattle, WA 565 566 Katherine G. Tarlock, MD, Pediatric Hematology/Oncology, Seattle Children’s Hospital and 567 University of Washington, Seattle, WA 568 569 Teresa K. Tarrant, MD, Rheumatology, Allergy and Immunology, University of North 570 Carolina, Chapel Hill, NC 571 572 Pierre Teira, MD, Pediatric Hematology/Oncology, Mother and Child Ste-Justine Hospital, 573 Montreal, Quebec, Canada 574 575 Monica Thakar, MD, Pediatric Bone Marrow Transplant, Children’s Hospital of Wisconsin, 576 Medical College of Wisconsin, Milwaukee, WI 577 578 Marie-France Vachon, RN, MScN, Mother and Child Ste-Justine Hospital, Montreal, Quebec, 579 Canada 580 581 Mark T. Vander Lugt, MD, Pediatric Hematology/Oncology, Children’s Hospital of 582 Pittsburgh, University of Pittsburgh Medical Center, PA

13 583 584 Jet van der Spek, Boston Children’s Hospital, Harvard Medical School, Boston, MA 585 586 Paul Veys, MD, Blood and Marrow Transplantation, Institute of Child Health, Great Ormond 587 Street Hospital, London, UK 588 589 Katja G. Weinacht, MD, PhD, Pediatric Hematology/Oncology, Boston Children’s Hospital, 590 Harvard Medical School, Boston, MA 591 592 Sheila Weiss, MS, Washington State Newborn Screening Laboratory, Department of Health, 593 Shoreline, WA 594 595 Lisa C. Winterroth, MD, Pediatric Allergy and Immunology, Seattle Children’s Hospital and 596 University of Washington, Seattle, WA 597 598 Ann E. Woolfrey, MD, Pediatric Hematology/Oncology, Seattle Children’s Hospital, Fred 599 Hutchinson Cancer Research Center and University of Washington, Seattle, WA 600 601 Joyce E. Yu, MD, Pediatric Allergy and Immunology, New York-Presbyterian Hospital, 602 Columbia University Medical Center, New York, NY 603 604 Lolie C. Yu, MD, MPH, Pediatric Hematology/Oncology, Children’s Hospital, LSU School of 605 Medicine, New Orleans, LA 606 607 Cecilia R. Zapata, MS, Seattle Cancer Care Alliance Network, Fred Hutchinson Cancer 608 Research Center, Seattle, WA 609 610 611 612

14 613 ELECTRONIC SUPPLEMENT REFERENCES 614 615 Table E5 References 616 617 E1. Zychlinski D, Schambach A, Modlich U, Maetzig T, Meyer J, Grassman E, et al. 618 Physiological promoters reduce the genotoxic risk of integrating gene vectors. Mol Ther. 2008; 619 16: 718-725. 620 621 E2. Hacein-Bey Abina S, Pai SY, Gaspar HB, Armant M, Berry CC, Blanche S, et al. A 622 modified gamma-retrovirus vector for X-linked severe combined immunodeficiency. New Engl J 623 Med. 2014; 371: 1407-1417. 624 625 E3. Zhou S, Ma Z, Lu T, Janke L, Gray JT, Sorrentino BP. Mouse transplant models for 626 evaluating the oncogenic risk of a self-inactivating XSCID lentiviral vector. PLoS One. 2013; 627 8(4): e62333. 628 629 E4. De Ravin SS, Gray JT, Throm RE, Spindler J, Kearney M, Wu X, et al. False-positive HIV 630 PCR test following ex vivo lentiviral gene transfer treatment of X-linked severe combined 631 immunodeficiency vector. Mol Ther. 2014; 22: 244-245. 632 633 E5. Candotti F, Shaw KL, Muul L, Carbonaro D, Sokolic R, Choi C, et al. Gene therapy for 634 adenosine deaminase-deficient severe combined immune deficiency: clinical comparison of 635 retroviral vectors and treatment plans. Blood. 2012; 120: 3635-3646. 636 637 E6. Gaspar HB. Gene therapy for ADA-SCID: defining the factors for a successful outcome. 638 Blood. 2012; 120: 3628-3629. 639 640 E7. Carbonaro Sarracino D, Tarantal AF, Lee CC, Martinez M, Jin X, Wang X, et al. Effects of 641 vector backbone and pseudotype on lentiviral vector-mediated gene transfer: studies in infant 642 ADA-deficient mice and rhesus monkeys. Mol Ther. 2014; 22: 1803-1816. 643 644 E8. Santilli G, Almarza E, Brendel C, Choi U, Beilin C, Blundell MP, et al. Biochemical 645 correction of X-CGD by a novel chimeric promoter regulating high levels of transgene 646 expression in myeloid cells. Mol Ther. 2011; 19: 122-132. 647 648 E9. Aiuti A, Biasco L, Scaramuzza S, Ferrua F, Cicalese MP, Baricordi C, et al. Lentiviral 649 hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome. Science. 2013; 650 341: 1233151. 651 652 E10. Bosticardo M, Ferrua F, Cavazzana M, Aiuti A. Gene therapy for Wiskott-Aldrich 653 syndrome. Curr Gene Ther. 2014; 14: 413-421. 654 655 E11. Hacein-Bey Abina S, Gaspar HB, Blondeau J, Caccavelli L, Charrier S, Buckland K, et al. 656 Outcomes following gene therapy in patients with severe Wiskott-Aldrich syndrome. JAMA. 657 2015; 313: 1550-1563. 658 659 660 661

15 662 Table E6 References

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22 970 TABLE E1. PIDTC PROTOCOLS AND CUMULATIVE ENROLLMENT Protocol 6901 (SCID Prospective) Year, January 1 – December 31 2010 2011 2012 2013 2014 2015 (through TOTAL June 30) CUMULATIVE Sites newly approved (opened) for 6 13 6 7 1 0 33 study participation (per year) Sites submitting potential patients 3 12 19 24 27 29 29 (cumulative) Patients submitted to PIDTC-SCID 6 24 35 44 40 24 173 RP (per year Subjects enrolled / approved by 6 21 36 38 40 27 168 PIDTC-SCID RP (per year; see note) Patients deemed ineligible by 0 0 1 3 1 0 5 PIDTC-SCID RP 971 V1.0 – 19 May 2010; V2.0 – 10 February 2011; V3.0 – 28 August 2012 972 From 19 May 2010, 33 North American PIDTC sites were eligible to participate in 6901; beginning 9/2014, 42 centers are 973 eligible. 974 Note: Patients reviewed in a given year may be approved for enrollment during the same year or the subsequent year, depending 975 on the timeframe of the review process. 976 Protocol 6902 (SCID Retrospective) Year, January 1 – December 31 2011 2012 2013 2014 2015 (through TOTAL June 30) CUMULATIVE Sites newly approved (opened) for 16 11 5 1 0 33 study participation (per year) Sites submitting potential patients 16 27 33 33 33 33 (cumulative) Patients submitted to PIDTC-SCID RP 209 240 205 180 1 835 (per year) Subjects enrolled / approved by PIDTC- 201 191 174 155 6 727 SCID RP (per year; see note) Patients deemed ineligible by PIDTC- 3 38 38 23 5 107 SCID RP 977 V1.0 – 30 November, 2010; V2.0 – 8 February 2012; V3.0 – 29 August 2012 978 From 30 November 2010, 33 North American PIDTC sites were eligible to participate in 6902; beginning September 2014, 42 979 sites are eligible. 980 Note: Patients reviewed in a given year may be approved for enrollment during the same year or the subsequent year, depending 981 on the timeframe of the review process. 982 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 TOTAL June 30) CUMULATIVE Sites submitting potential patients 2 6 13 18 19 19 (cumulative) Subjects enrolled /signed 6902 XS 27 28 25 13 6 100 consent (per year) 983 V1.0 – 30 November, 2010; V2.0 – 8 February 2012; V3.0 – 29 August 2012 984 From 30 November 2010, 33 North American PIDTC sites were eligible to participate in 6902; beginning September 2014, 42 985 sites are eligible. 986 XS, Cross-Sectional

23 987 Protocol 6903 (CGD) Year, January 1 – December 31 2014 2015 (through TOTAL June 30) CUMULATIVE Sites newly approved (opened) for study participation (per year) 9 18 27 Sites submitting potential patients (cumulative) 1 9 9 Patients submitted to PIDTC-CGD RP (per year) 2 77 79 Subjects enrolled / approved by PIDTC-CGD RP (per year) 2 68 70 Patients deemed ineligible by PIDTC-CGD RP 0 0 0 988 V1.0 – 23 December 2013 989 From 23 December 2013, 33 North American PIDTC sites were eligible to participate in 6903; beginning September 2014, the 990 total is 45 sites; 42 of these are North American, and 3 are European. 991 Note: Patients reviewed in a given year may be approved for enrollment during the same year or the subsequent year, depending 992 on the timeframe of the review process. 993 994 Protocol 6904 (WAS) Year, January 1 – December 31 2014 2015 (through TOTAL June 30) CUMULATIVE Sites newly approved (opened) for study participation (per year) 16 13 29 Sites submitting potential patients (cumulative) 3 11 11 Patients submitted to PIDTC-WAS RP (per year) NA 21 21 Subjects enrolled / approved by WAS-SCID RP (per year) NA 21 21 Patients deemed ineligible by PIDTC-WAS RP 0 0 995 V1.0 - 28 October 2013 996 From 28 October 2013, 33 North American PIDTC sites were eligible to participate in 6904; beginning September 2014, 42 sites 997 are eligible. 998 Note: Patients reviewed in a given year may be approved for enrollment during the same year or the subsequent year, depending 999 on the timeframe of the review process. 1000 NA, not applicable. 1001 1002 1003 1004

24 1005 TABLE E2. Goals and Significance of PIDTC Workshops Sponsor Workshop (Reference) Goals and Significance PIDTC Radiation-sensitive severe Defects in DNA repair pathways which Workshop combined immunodeficiency: the recognize and repair nonprogrammed DNA Debate arguments for and against double-strand breaks (DSBs) have potential to 2013 conditioning before hematopoietic compromise genomic integrity, and result in cell transplantation – what to do? radiation-sensitive SCID. For some of these (Cowan MJ, Gennery AR. J genotypes, exposure to alkylator therapy also Allergy Clin Immunol. 2015; 136: appears to be associated with decreased 1178-1185.) 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 Primary Immune Deficiency The PIDTC is a network of 33 centers in North Workshops, Treatment Consortium (PIDTC) America that care for patients with PID. The 2011 & 2012 report. (Griffith LM, Cowan MJ, objectives and progress to date of PIDTC Notarangelo LD, et al. J Allergy natural history protocols are summarized. Clin Immunol. 2014; 133: 335-347.) 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 B-cell reconstitution for SCID: Reconstitution of T-cells is reliably achieved Workshop should a conditioning regimen be following allogeneic HCT for SCID, whereas Debate used in SCID treatment? (Haddad reconstitution of B-cells is problematic. 2012 E, Leroy S, Buckley RH.J Allergy Factors important for B-cell reconstitution Clin Immunol. 2013; 131: 994- include genotype of the SCID defect, and use of 1000.) a conditioning regimen containing busulfan. The risks and benefits of conditioning to achieve B-cell reconstitution are considered. PIDTC Survey on re-transplantation criteria In spite of their immunodeficiency, patients Practice for patients with severe combined with SCID may experience graft loss or failure Survey immunodeficiency. (Haddad E, to engraft following allogeneic HCT, especially 2011 Allakhverdi, Z, Griffith LM, Cowan given the goal to use no or minimal MJ, Notarangelo LD. J Allergy Clin conditioning in these vulnerable young patients. Immunol. 2014; 133: 597-599.) The criteria used to define failure of HCT and decide when to re-transplant are summarized. NIH - NIAID Improving cellular therapy for PIDTC investigators assembled their collective & ORDR, primary immune deficiency expertise in management of patients with PIDs NCATS diseases: recognition, diagnosis, and before, during and after HCT, to develop Workshop management. (Griffith LM, Cowan guidance documents for their colleagues who 2009 MJ, Notarangelo LD, Puck JM, care for these patients. Buckley RH, Candotti F, et al. J

25 Allergy Clin Immunol. 2009; 124: 1152-1160.e12.) NIH - NIAID Allogeneic hematopoietic cell Determine feasibility of natural history studies & ORDR, transplantation for primary immune to evaluate outcomes of HCT for PID in North NCATS deficiency diseases: current status America, identify expertise needed to undertake Workshop and critical needs. (Griffith LM, such investigations, and propose key diseases 2008 Cowan MJ, Kohn DB, Notarangelo and research questions. Although allogeneic LD, Puck JM, Schultz KR, et al. J HCT has been used to treat PID for 40 years, Allergy Clin Immunol. 2008; 122: this is the first effort to organize a collaborative 1087-1096.) 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. 1006 1007 1008 1009 1010

26 1011 TABLE E3. PIDTC Pilot Project Awards Award Investigator and Project PIDTC Presentation (Year) Year Institution and/or Publication 2009- Jennifer Puck MD, SCID diagnosed by newborn Presentation (2011, 2012, 2011 UCSF, San Francisco, screening in Navajo Native 2014) CA Americans. 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- Sung-Yun Pai MD, Recovery of CD19+ B-cell Presentation (2014) 2013 Childrens Hospital of development and function after Boston, Boston, MA hematopoietic stem cell transplant for SCID. 2014 Hélène Decaluwe MD, T cell exhaustion in SCID after Presentation (2014, 2015) PhD, and Francoise Le hematopoietic stem cell Deist, MD, Mother and transplant Child Ste-Justine Hospital, Montreal, QC, Canada 2015- David Rawlings MD, Investigation of the molecular Presentation (2015) 2016 Seattle Children’s and cellular mechanisms of Hospital, Seattle, WA autoimmunity in patients with Wiskott-Aldrich syndrome undergoing hematopoietic stem cell transplant 1012 1013

27 1014 TABLE E4. PIDTC Fellowship Awards Award Investigator and PIDTC Workshop Presentation (Year) and Publication Year Institution 2009 Shirley Becker-Herman, Presentation: NA PhD, Seattle Children’s Publication: Becker-Herman S, Meyer-Bahlburg A, Research Institute, Seattle, Schwartz MA, Jackson SW, Hudkins KL, Liu C, et al. WA 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; Presentation (2011): The mechanism of etoposide activity in Cincinnati Children’s hemophagocytic lymphohistiocytosis Hospital Medical Center, Publication: Johnson TS, Terrell CE, Millen SH, Katz JD, Cincinnati, OH 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; Presentation (2011): Immunodeficiency relational database Childrens Hospital of Database: www.immunodeficiencysearch.com Philadelphia, PA 2010 Heather Stefanski MD,PhD; Presentation (2011): Utilizing T progenitors to improve University of Minnesota immune reconstitution in primary immunodeficiency Medical Center, Publication: Taylor PA, Kelly RM, Bade ND, Smith MJ, Minneapolis, MN 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 Presentation (2012): Dendritic cell activation and migration College of Medicine, after allergen challenge in CGD mice Houston, TX 2011 Jacob Rozmus MD; BC Presentation (2012): Using biomarkers to help us better Childrens Hospital, understand the pathophysiology of chronic graft-versus-host Vancouver, BC, Canada 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- Presentation (2013): Mesenchymal cells modulation of Justine, Montreal, Quebec, immune regulation of monocytes, macrophages and dendritic Canada cells Publication: 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; Presentation (2013): Dysregulated BCL-2 pathway in Cincinnati Children’s autoimmune lymphoproliferative syndrome (ALPS)

28 Hospital Medical Center, Publication: Niss O, Sholl A, Bleesing JJ, Hildeman DA. IL- Cincinnati, OH 10/Janus kinase/signal transducer and activator of transcription 3 signaling dysregulates Bim expression in autoimmune lymphoproliferative syndrome. J Allergy Clin Immunol. 2015; 135: 762-770. 2012- Katja Weinacht MD,PhD; Presentations (2013, 2014): Disease modeling for reticular 2013 Children’s Hospital Boston, dysgenesis (mutation of AK2 gene) with induced pluripotent Harvard Medical School, stem cells (iPS) Boston, MA 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- Caroline Kuo MD; UCLA Presentations (2013. 2014, 2015): Targeted gene therapy in 2013 Mattel Childrens Hospital, the treatment of X-linked hyper-IgM syndrome (CD40 and Los Angeles, CA ligand deficiency) using TALENS 2014 2014 Teresa Tarrant MD; Presentation (2015): Interrogating genetic susceptibility University of North Carolina loci in CVID with autoimmunity School of Medicine, Chapel Publication: Burbank AJ, Shah SN, Montgomery M, Peden Hill, NC 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 Presentation (2015): Development of a gene therapy model Hospital, University of for DOCK 8 deficiency Minnesota School of Medicine, Minneapolis, MN 2015 Paul Maglione, MD; Icahn Presentation (2015): Elucidating the role of BAFF in CVID School of Medicine at interstitial lung disease Mount Sinai, New York, NY 1015 1016 Note: NA, not applicable.

29 1017 TABLE E5. Gene Transfer Studies in PID Currently Open and Planned XSCID Center Sponsor(s) Vector Treatment Publications Regimen “XSCID-2” Parallel US Funding: Virus: Gamma retrovirus, Conditioning: References: Includes Parallel European NIAID deleted of LTR enhancer None Zychlinski et al EU Study and North (D. Williams). elements, with transgene (2008),E1 American expression mediated by a Hacien-Bey Activation Date: studies. UK: NHS cellular promoter. Abina et al 2011; recruiting US: Boston, Foundation Trust Insert: IL2R gamma chain (2014)E2 Cincinnati, (A. Thrasher) Modifications: WPRE post- Registration: Los Angeles; translational regulatory ClinicalTrials.gov EU: London, FR: Assistance element to enhance expression NCT01129544 Paris. Publique- Safety modifications: EFS (London & Hopitaux Paris (EF1 alpha short) cellular Paris); (A. Fischer) internal promoter; U3 deletion ClinicalTrials.gov in LTR (SIN configuration) NCT01175239 Vector development: C. Baum, (Boston, Hannover, Germany Cincinnati, Los Vector manufacture: Angeles). Cincinnati Target: BM CD34+ cells

US IND: D. Williams, Children’s Hospital Boston Activation Date: St. Jude, Funding: NHLBI Virus: Lentivirus Conditioning: References: 2012 recruiting Memphis, (B. Sorrentino) Insert: IL2R gamma chain None initially; Zhou et al TN Safety modifications: EFS modified for low (2013)E3 Registration: (EF1 alpha short) cellular dose busulfan ClinicalTrials.gov internal promoter; U3 deletion NCT01512888 in LTR (SIN configuration); enhancer blocking insulator sequence(s) Vector development: St. Jude- B. Sorrentino Target: BM CD34+ cells

Proposed Parallel Proposed US Virus: Lentivirus Conditioning: References: “XSCID-3” European Funding: NIAID Insert: IL2R gamma chain Propose to This study will Includes Parallel and North (S.-Y. Pai) Safety modifications: EFS include reduced be the next EU Study American (EF1 short) cellular internal intensity generation studies. US: UK: NHS promoter; U3 deletion in LTR conditioning study to follow Activation Date: Boston Foundation Trust (SIN configuration);enhancer Hacien-Bey- In development Children’s (A. Thrasher) blocking insulator sequence(s) Abina et al Hospital; UC Vector manufacture: Genethon, (2014)E2 Los Angeles. Switzerland: Paris, FR EU: Great Pending Target: BM CD34+ cells Ormond Street Netherlands: US IND: D. Williams, Hospital, Pending Children’s Hospital Boston London; EU IND: EU will have a Zurich; and separate regulatory package, Leiden. and Genethon will hold the EU IND. XSCID in Center Sponsor(s) Vector Treatment Publications Older Regimen Children Activation Date: NIH Clinical Funding: NIH Virus: Lentivirus Conditioning: References: 2010, recruiting Center Clinical Center & Insert: IL2R gamma chain Busulfan De Ravin et al /Intramural Intramural Safety modifications: EFS 6mg/kg (2014)E4

30 Registration: NIAID NIAID (EF1 short) cellular internal Clinical (S. S. DeRavin, promoter; U3 deletion in LTR Trials.gov H. Malech) (SIN configuration);enhancer NCT01306019 blocking insulator sequence(s) Target: CD34+ mPBSC Vector development: St. Jude -B. Sorrentino ADA SCID Center Sponsor(s) Vector Treatment Publications Regimen Activation Date: UCLA, NIH Funding: NIAID Virus: Lentivirus PEG-ADA: References: May 2013 Clinical (D. Kohn) Insert: ADA gene Discontinue day Candotti et al Recruiting Center Modifications: codon +30. (2012),E5 /Intramural optimized human ADA cDNA, Conditioning: Gaspar Registration: NHGRI WPRE post-translational Myeloreductive (2012),E6 ClinicalTrials.gov regulatory element to enhance Busulfan (4 Carbonaro- NCT01852071 US and expression mg/kg) Sarracino London UK Safety modifications: EFS (2014)E7 are parallel (EF1 alpha short) cellular studies (see internal promoter; U3 enhancer below). deletion in LTR (SIN configuration) Vector manufacture: IUVPF Target: BM CD34+ cells Activation Date: London UK: NHS Virus: Lentivirus PEG-ADA: References: 2012 GOSH, UK Foundation Trust Modifications: codon Discontinue day Gaspar Recruiting (A. Thrasher) optimized human ADA cDNA, +30 (2012),E6 US and WPRE post-translational Conditioning: Carbonaro- Registration: London UK regulatory element to enhance Myeloreductive Sarracino et al ClinicalTrials.gov are parallel expression Busulfan (4 (2014)E7 NCT01279720 studies (see Safety modifications: EFS mg/kg) above). (EF1 alpha short) cellular internal promoter; U3 enhancer deletion in LTR (SIN configuration) Vector manufacture: IUVPF Target: BM CD34+ cells; if > 5 kg mobilize PBSC Proposed UC Los US Funding: Virus: Lentivirus PEG-ADA: References: Activation Date: Angeles; NIAID Modifications: codon Discontinue day This will be the In development London (D. Kohn). optimized human ADA cDNA, +30. licensure study, WPRE post-translational Conditioning: to follow the This will be a US and UK: NHS regulatory element to enhance Myelo-reductive studies phase 3 licensure London, UK Foundation Trust expression Busulfan (4 immediately study will be (A. Thrasher) Safety modifications: EFS mg/kg). above. parallel (EF1 short) cellular internal studies promoter; U3 enhancer deletion in LTR (SIN configuration) Vector manufacture: IUVPF Target: BM CD34+ cells; if > 5 kg mobilize PBSC

Orphan Drug Registration status for vector received from FDA October 2014 XCGD Center Sponsor(s) Vector Treatment Publications Regimen Proposed US UC Los Proposed US Virus: Lentivirus Conditioning: References: Study Angeles; Funding: CIRM Insert: gp91phox pK targeted Santilli G et al NIH Clinical (D. Kohn); NIH Safety modifications: Busulfan (2011)E8 Activation Date: Center Clinical Center & Regulated promoter (chimeric

31 In development /Intramural Intramural CatG/cFes promoter with NIAID, NIAID mutated TATA box contains Bethesda; (E. Kang/ binding sites for transcription Boston H. Malech) factors needed for commitment Children’s & differentiation myeloid cells Hospital. to granulocyte lineage) Vector manufacture: Genethon, US and EU Paris, FR subjects will Target: CD34+ mPBSC be a combined US: D. Kohn, UC Los Angeles safety - IND approved by FDA as of database. November 2014, and will open protocol in January 2015 Graft Manufacture in US: DFCI GMP facility is lead and will train & qualify other sites

Proposed EU 4 sites - EU funding Virus: Lentivirus Conditioning: References: Study – Parallel Germany; Insert: gp91phox pK targeted Santilli G et al to US Study London, UK; UK: NHS Safety modifications: Busulfan (2011)E8 Zurich, Foundation Trust Regulated promoter (chimeric Activation Date: Switzerland; (A. Thrasher) CatG/cFes promoter with In development and Paris, mutated TATA box contains France. binding sites for transcription factors needed for commitment EU & US & differentiation myeloid cells studies to granulocyte lineage) parallel & Vector manufacture: Genethon, independent. Paris, FR. New European vector construct will be the same for the EU and US studies. Target: CD34+ mPBSC

WAS Center Sponsor(s) Vector Treatment Publications Regimen EU Study London, UK; US funding for Virus: Lentivirus Pre- References: -Includes US Paris, Boston site: Insert: WASp Conditioning: Aiuti et al Boston Site France; GTRP, NHLBI Modifications: WPRE post- Anti-CD20 (2013),E9 Milan, Italy; (D. Williams) translational regulatory monoclonal Ab. Bosticardo et al Activation Date: Boston, USA element to enhance expression Conditioning: (2014),E10 2010 (Milan); UK: NHS Safety modifications: hWAS Reduced Hacein-Bey 2011 (London, Foundation Trust endogenous promoter intensity Abina et al Paris, Boston); (A. Thrasher) Vector manufacture: Genethon, Busulfan 8-12 (2015)E11 recruiting Paris, FR; mg/kg, FR:Assistance Target: CD34+ mPBSC Fludarabine 120 Registration: Publique- mg/m2; ATG if ClinicalTrials.gov Hopitaux Paris autoimmune NCT01347242 (A. Fischer); manifestations (London); French National ClinicalTrials.gov Registry for NCT01347346 Primary Immuno- (Paris) deficiencies; ClinicalTrials.gov Genethon. NCT01515462 (TIGET, Milan); IT: Fondazione ClinicalTrials.gov Telethon (TIGET NCT01410825 core grant to A. (Boston). Aiuti and others) and the European

32 Commission (M.- G. Roncarolo, A. Aiuti and L. Naldini), Italian Ministero della Salute. 1018 1019 Notes: 1020 Retrovirus and lentivirus vectors are used in PID; adenovirus and AAV vectors are not persistent in 1021 proliferating bone marrow stem cells and lymphocytes (so cannot be used for GT for PID). 1022 The necessity to transfect CD34 ex vivo or lymphocytes ex vivo is cumbersome, but relatively effective. 1023 MLV = Moloney murine leukemia virus; MFG or MFGS = MLV vector with MLV LTR and MLV 1024 envelope splice acceptor site (Malech group); MND = MPSV LTR, negative control region deleted, 1025 dl587 primer binding site substituted (Kohn group); SF = or SFFV = spleen focus forming virus LTR. 1026 IUVPF = Indiana University Vector Production Facility, CIRM=California Institute for Regenerative 1027 Medicine. 1028 1029

33 1030 TABLE E6. Emerging Indications for HCT in PID (Selected) Indication Disease Mechanism Disease HCT HCT and and Incidence Outcomes Comments References Clinical Features Combined T Cell and B Cell Immunodeficiencies STAT1 GOF AD STAT-1 GOF mutations Twelve (12) AD Four (4) patients HCT appears to impair nuclear STAT-1 GOF have been have clinical Mutation: dephosporylation of activated mutations have been transplanted benefit. STAT1 STAT-1 and thereby IL-17 described E12 (personal immunity. Patients experience communication), Unclear if mixed References: chronic mucocutaneous all are surviving chimerism is Liu et al (2011)E12 candidiasis and other as of July 2015. sufficient for infections, and autoimmunity. resolution of infections. STAT3 GOF Mutations confer GOF in Nine (9) different Three (3) patients HCT appears to STAT-3 leading to secondary heterozygous have received have clinical Mutation: defects in STAT-5 and STAT- mutations in STAT-3 HCT (personal benefit. STAT3 1 phosphorylation and the have been described in communication), regulatory T-cell 13 individuals from 10 all are surviving References: compartment. Patients families E13 as of July 2015. Milner et al (2015)E13 experience infections and autoimmunity including type 1 Patients have 80- diabetes, and autoimmune 100% donor thyroid, pulmonary and chimerism and arthritic disease. appear improved clinically. STAT3 LOF (AD- LOF mutations in STAT3 Multiple individuals Five (5) patients HCT appears to Hyper-IgE Syndrome cause reduced numbers of having STAT-3 LOF have been have clinical (HIES) / Job peripheral blood mucosal have been described transplanted benefit. Syndrome) associated invariant T-cells recently.E14 (personal and natural killer T-cells. communication); Mutation: Patients experience recurrent all are surviving STAT3 infections including cutaneous as of July 2015. viral infections, abscesses and References: pulmonary complications, Four (4) of 5 Wilson et al (2015)E14 with characteristic skeletal patients have 95- abnormalities. 100% donor chimerism, with improvement in clinical condition; 1 patient is recently post- HCT. IFNGR1 Autosomal Response to IFN-γ is Thirty-eight (38) One (1) patient HCT appears to Partial Dominant impaired. Mutant protein is patients with IFNGR1 with course have clinical Deficiency (IFN more stable than WT and does partial dominant complicated by benefit. Gamma Receptor-1) not signal. Patients are deficiencies have been multifocal susceptible to BCG and identified and osteomyelitis due Mutation: environmental mycobacterial reviewed.E15 to M. para- IFNGR1 infections, including M. avium Additional cases have scrofulaceum and complex osteomyelitis. been described.E16 marginal zone B- References: cell lymphoma is Dorman et al (2004),E15 recently post- Sharma et al (2015)E16 HCT as of July 2015; treatment for recurrent lymphoma has been needed (personal

34 communication). DOCK2 AR LOF RAC1 activation is impaired Five (5) unrelated Three (3) of the 5 HCT appears (Dedicator of in T-cells. Chemokine- children with this patients described potentially Cytokinesis 2) induced activation and actin genetic defect have received HCT curative. polymerization are defective recently been and are well; the Mutation: in T-cells, B-cells, and NK- described.E17 other 2 did not DOCK2 cells, and NK-cell receive HCT and degranulation is affected. Due died in early References: to lymphopenia and defective childhood.E17 Dobbs et al (2015)E17 T-cell, B-cell and NK-cell responses, children develop early-onset invasive bacterial and viral infections. Early diagnosis is critical. DOCK8 Deficiency AR hyper-IgE syndrome with One hundred thirty-six Of the 136 Consideration of (Dedicator of CID is a cellular (136) patients have patients reported, early HCT is Cytokinesis 8) immunodeficiency. The recently been 36 patients recommended as underlying CID affects B- examined in an received HCT a potential Mutation: cells, NK cells, and CD8 international and detailed curative DOCK8 subsets of T-cells. Patients are retrospective surveyE18 analysis is measure. predisposed to cutaneous viral underway; other References: infections; complications reports of Aydin et al (2015),E18 including severe life- treatment with Cuellar-Rodriguez et al threatening infections, HCT are (2015),E19 Notarangelo malignancy and stroke referenced. E18 (2013)E20 constitute severe morbidity HCT for an and adversely affect mortality. additional 6 patients has recently been reported. E19 CARD-11 CARD-11 is a member of the Three (3) patients in 2 All 3 patients Early (CARMA-1) AR LOF CBM signalosome complex families having have received therapeutic (Caspase Recruitment which also includes BCL-10 germline mutation of curative HCT. E21 allogeneic HCT Domain Family, and MALT-1. E21 Germline CARD-11 have been is Member 11) mutations of the CBM reported. E21 recommended. complex cause novel CID Mutation: phenotypes with abnormal CARD11 NFkB activation after B-cell and T-cell antigen receptor References: stimulation. Patients have Turvey et al (2014)E21 normal T cell numbers with Stepensky et al (2013)E22 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. BCL-10 AR LOF (B- BCL-10 is a member of the A single case has been One patient has Based on BCL- cell CLL / Lymphoma CBM signalosome complex. reported. E23 been described; 10 biology, 10) Normal T cell numbers with the patient did not restoration of abnormal proliferation, receive HCT. immune Mutation: dysregulated B cell function by BCL10 development, and fibroblast HCT should be defects may be present. possible. References: Torres et al (2014)E23 MALT-1 AR LOF MALT-1 is a member of the Three (3) cases are One (1) patient Based on

35 (Mucosa Associated CBM signalosome complex. reviewed;E21,E24,E25 and has received MALT-1 Lymphoid Tissue Patients have normal T cell 1 case is reported.E26 successful biology, Lymphoma numbers with abnormal HCT.E26 restoration of Translocation proliferation, and dysregulated immune Gene-1) B cell development. MALT-1 function by deficient patients experience HCT should be Mutation: severe CID with possible. MALT1 gastrointestinal inflammation. Note, TREC-based NBS may References: fail to identify affected Turvey et al (2014),E21 individuals. TCR stimulation- Jabara et al (2013),E24 induced proliferation, and McKinnon et al additional specific tests should (2014),E25 be pursued. Punwani et al (2015)E26 IKK2 / IKKBeta AR IKK-2 is a component of the Four (4) patients from Three (3) of the HCT appears LOF (IKK2 SCID) IKK-nuclear factor kB (NF- 4 families of Northern patients reported promising. kB) pathway. B-cell and T-cell Cree, E27 1 patient from by Pannicke et al Mutation: counts are normal, almost the Arabian Peninsula, (2013) E27 IKBKB exclusively of naïve E28 1 patient of Turkish received HCT, phenotype, and have impaired descent E29 and 4 and 2 survived References: responses to mitogens. patients from 2 with Pannicke et al (2013),E27 Patients have different Qatari improvement of Burns et al (2014),E28 hypogammaglobulinemia / families E30 have been their clinical Nielsen et al (2014),E29 agammaglobulinemia and reported. condition. Mousallem et al early onset of severe IKK-related genetic (2014),E30 infections. diseases have been Senegas et al (2015)E31 reviewed. E31 CTPS-1 AR LOF This mutation is a defect of Eight (8) children Of 6 who Allogeneic HCT (Cytidine 5’ the pyrimidine pathway. from 5 families in received HCT, 4 appears Triphosphate Activated T-cells and B-cells northwest England survived, with promising. Synthetase-1) have decreased levels of CTP have been reported. E32 improvement in and impaired proliferative their clinical Mutation: responses to antigen receptor- condition E32. CTPS1 mediated activation. Patients experience early onset severe References: chronic viral infections mostly Martin et al (2014)E32 caused by herpes viruses. Immunoglobulin Class Immunoglobulin isotype The prevalence of the The first case Allogeneic HCT Switch Recombination switching is impaired due to disease has been report of HCT for is curative if Deficiencies (CD40 defects in the CD40 ligand / reviewed. E33,E34 CD40LG performed prior Ligand Deficiency / X- CD40 signaling pathway. X- deficiencywas to onset of life- Linked Hyper IgM linked forms are due to defects reported in threatening Syndrome; HIGM) in the CD40 ligand gene or 1995.E35 European complications of NF-kB essential modulator; experience of 38 disease. Mutation: AR forms are due to defects in cases from 8 CD40 Ligand (CD40LG, CD40 or downstream countries has also called TNFRSF5) signaling molecules.E34 been reported, E36 and there are References: several Johnson et al (2007, subsequent update 2013),E33 reports. Qamar et al (2014),E34 Collaborative Thomas et al (1995),E35 efforts to Gennery et al (2004)E36 summarize the retrospective HCT experience are underway: IEWP-EBMT & PIDTC; and Morena et al (unpublished).

36 MHC Class II HLA Class II gene expression About 200 patients Six of the patients HCT is currently Deficiency AR LOF is lacking, with absence of T- have been reported reported by the only curative (Bare Lymphocyte cell and B-cell immune worldwide, the Saleem et treatment, and is Syndrome, Type II) response to foreign antigens, majority of North al(2000)E38 considered the and impaired antibody African origin.E37 received HCT treatment of Mutations: production. The genetic basis Reports include 10 and 2 survived; choice;E39 Transcription factors is the result of mutations in children from 8 23 of the patients transplant at a for MHC Class II genes coding for transcription kindreds E38 and 35 reported by young age is proteins: CIITA, RFX5, factors that normally regulate patients from 30 Ouederni et recommended. RFXAP; RFXANK the expression of the MHC II kindreds.E39 al(2011)E39 genes (CIITA and subunits of received HCT References: RFX). Patients usually and 10 were Hanna et al (2014),E37 present with clinical findings cured with Saleem et al (2000),E38 of CID, and experience recovery of Ouederni et al (2011)E39 extreme susceptibility to viral, almost normal bacterial and fungal infections. immune MHC Class II deficiency may functions. account for about 5% of typical SCID. PI3K Delta GOF Defects in T-cell function with Seven unrelated HCT has been HCT may be (Phosphaditylinositol-3- deficiency of naive T cells and families with 17 used in 1 patient effective. OH Kinase Delta an excess of senescent effector affected individualsE40 successfully, but Catalytic Subunit) T cells. Defects in B-cell and a single family long-term data (Activated PI3K Delta function with increased IgM, with 5 affected regarding Syndrome; APDS) reduced IgG2, and impaired individuals E41 have efficacy is not yet vaccine responses. Patients been described. available. E41 Mutation: experience recurrent PIK3CD sinopulmonary infections, progressive airway damage, References: CMV and EBV viremia and Angulo et al (2013)E40 lymphoproliferation. Hartman et al (2015)E41 ZAP-70 (Zeta Chain ZAP-70 is a tyrosine kinase Karaca et al(2013)E42 Allogeneic HCT HCT is the only (TCR) Associated associated with the zeta chain have summarized has been curative Protein Kinase 70) of the TCR, and undergoes reports of 12 cases successfully used treatment phosphorylation upon TCR with ZAP-70 in several available. Mutation: activation. Deficiency leads to mutations leading to cases.E43 One such ZAP70 abnormal thymic development SCID and related case E44 and an and abnormal T-cells in the phenotypes. In total, additional caseE45 References: periphery, including absence about 20 patients from have been Karaca et al (2013),E42 of CD8+ T-cells and anergic different families have reported. Fischer et al (2010),E43 CD4+ T-cells unresponsive to been described. E43 Barata et al (2001),E44 mitogens. Patients have failure Fagioli et al (2003)E45 to thrive and early onset of severe life-threatening infections. Predominantly Antibody Deficiencies Common Variable CVID is immunologically and Incidence of CVID is Wehr et al E46 HCT can be Immunodeficiency genetically heterogeneous, high among the PID, have studied curative, and (CVID) with hypogammaglobulinemia between 1:10,000 and outcomes of HCT investigation as (Hypoglobulinemia of at least 2 immunoglobulin 1: 50,000. for 25 patients therapy for a with Normal / Low isotypes. The severity of with CVID. subgroup of Number of B Cells) disease may correlate with patients with aspects of T-cell deficiency. CVID having Mutations: Patients experiencing only complicated Various; heterogeneous infections may have normal course with high life expectancy; in contrast, mortality is References: those with comorbidities warranted. Wehr et al (2015)E46 including splenomegaly, granuloma, autoimmunity, enteropathy, liver disease, interstitial lung disease or

37 neoplasia have compromised life expectancy. Phagocyte Defects GATA 2 Deficiency GATA-2 is a zinc finger GATA-2 has now Of 14 patients The underlying (MonoMAC Syndrome) hematopoietic transcription been reported as the who received defect is bone factor critical for embryonic cause of many diverse HCT, 8 are alive marrow Mutation: and definitive hematopoiesis, phenotypes, which with dysfunction. GATA2 and for lymphatic suggests that reconstitution of HCT has been angiogenesis. Heterozygous additional phenotypes deficient cellular successful for References: mutations appear to cause may emerge. E47 populations and both hemato- Hsu et al (2015),E47 haploinsufficiency due to reversal of the poietic and Grossman et al (2014),E48 either protein dysfunction or clinical pulmonary Cuellar-Rodriguez et al uniallelic reduced phenotype at alveolar (2011)E49 transcription.E47 Severely median follow-up proteinosis deficient monocyte, B-cell and of 3.5 years; 2 repair. NK-cell populations are patients rejected present. Patients have various the graft and 1 phenotypes including viral and relapsed with bacterial infections, MDS after cytopenias, myelodysplasia, transplantation.E48 myeloid leukemias, pulmonary Of 6 additonal alveolar proteinosis and patients, E49 5 had lymphedema.E47 corrected monocyte, B-cell and NK-cell counts with improvement of the clinical phenotype at median follow-up of 17.4 months. Genetic Disorders of Immune Regulation CTLA4 / CD152 Haploinsufficiency of human Heterozygous One (1) patient HCT appears (Cytotoxic T CTLA-4 causes dysregulation mutations from 6, E50 was transplanted promising. Lymphocyte Antigen-4) of FoxP3+ regulatory T-cells, and from 4 E51 over 1 year ago Haplo-insufficiency hyperactivation of effector T unrelated families (personal cells, and lymphocytic have been identified. communication), Mutation: infiltration of target organs.E51 and is currently CTLA4 Patients have an immune surviving. The dysregulation syndrome with patient has 100% References: hypogammaglobulinemia, donor chimerism Schubert et al (2014),E50 recurrent infections and and is clinically Kuehn et al (2014)E51 multiple autoimmune clinical improved at last features.E50 follow up. LRBA Deficiency Patients have Homozygous One (1) patient is HCT may (Lipopolysaccharide- hypogammaglobulinemia, mutations have been reported to have have promise; Responsive Beige-Like infections and autoimmunity, identified in 4 received HCT;E53 E52 further Anchor Protein) such as inflammatory bowel families, and in 1 1 additional investigation is disease and autoimmune family. E53 patient has also Mutation: cytopenias. been transplanted needed. LRBA (personal communication). References: Both are currently Lopez-Herrera et al surviving and (2012),E52 have 100% donor Seidel et al (2015)E53 chimerism. However the first patient E53 subsequently developed ITP refractory to

38 therapy, and the second also continues to have complications. Familial HLH (FHL-1 Genes and proteins affected Among 175 adult HCT for 86 cases In patients through FHL-5; are described in Table 1 of patients with HLH, of HLH with genetic E54 Includes Perforin, Janka et al (2013). All of the hypomorphic (including 29 HLH, HCT is Munc 13-4, Syntaxin FHL genes are involved in monoallelic or FHL cases) has curative for the 11, and Munc 18-2 cytotoxic granule exocytosis biallelic mutations in been described.E56 Defects) or function. HLH is a FHL genes were Outcomes of immune hyperinflammatory syndrome found in 14%.E55 HCT for an defect. RIC Mutations: caused by excessive activation additional 48 may be Include: PFR1, of lymphocytes and cases of FHL preferred due UNC13D, STX11, macrophages with high levels have been to increased STXBP2 (UNC18B) of cytokines; symptoms examined. E57 mortality with include cytopenias; HLH has Remission of MAC References: high mortality even with HLH prior to regimens.E58 Janka et al (2013),E54 appropriate treatment. HCT is desirable. Zhang et al (2011),E55 Horne et al (2005),E56 Ouachee-Chardin et al (2006),E57 Marsh et al (2010)E58 HLH and XLP Genes and proteins affected XLP-1 is rare among HCT is often For XLP-1, Associated with are described in Table 1 of PID; management and performed to HCT has been Immunodeficiency Janka (2013).E54 Processing of outcome have been improve long E59 shown to have Syndromes (XLP-1, cytotoxic vesicles is impaired. described. term survival. benefit, and is XLP-2; Includes SAP XLP-1 is commonly Outcomes of and XIAP Defects) characterized by fulminant HCT have been associated EBV infection and/or HLH described for 43 with resolution Mutations: after EBV infection, B-cell patients with of HLH and Include: LYST, lymphoma, and other XLP-1.E59 Use of lymphoma.E60 RAB27A, SH2D1A, complications. RIC for 16 HCT for XLP- BIRC4 patients with 2 should be XLP-1 from a based on the References: single center, E54 severity of the Janka et al (2013), with 80% 1-year clinical course. Booth et al (2011)E59 OS, and 71% Marsh et al (2014),E60 long-term survival, has been described.E60 Autoimmune Germline defects of FAS are Prevalence of ALPS is Experience with HCT may be Lymphoproliferative the most commonly identified unknown. A HCT for ALPS is indicated for E61,E62 Syndrome (ALPS) abnormality in ALPS. distinction needs to be limited; case those with ALPS is characterized by made between reports severe clinical Mutation: immune dysregulation due to presence of the demonstrating FAS (two-thirds of inability to regulate cellular phenotype correction of the phenotypes patients); and lymphocyte homeostasis (defective FAS- clinical (ALPS-FAS), undefined through abnormalities in mediated apoptosis) phenotype for 3 severe and/or apoptosis. Expansion of T- and penetrance of the patients have refractory References: cells that have the alpha/beta clinical phenotype been cytopenias, or Shah et al (2014),E61 TCR, but lack both CD4 and (ALPS). Factors published.E63-E65 lymphoma. Bleesing et al (2006, CD8, and defective FAS- determining RIC regimens E62 update 2014), mediated apoptosis in vitro is penetrance of clinical may be a Dimopoulou et al typical. Patients have ALPS are not realistic option (2007),E63 lymphoproliferative and presently Sleight et al (1998),E64 autoimmune diseases. understood.E62 for patients Benkerrou et al (1997)E65 with comorbidities due to the disease. Immuno-dysregulation, IPEX is due to germline Extremely rare; no At least 28 HCT is needed

39 Polyendocrinopathy, mutations in the FOXP3 gene, estimates of incidence patients have for correction Enteropathy, X-Linked a master transcriptional have been proposed. received HCT for of the immune (IPEX) regulator for development of IPEX; 6 died of defect. Early CD4 regulatory T-cells (Treg). disease or during HCT leads to Mutation: Patients experience severe, conditioning; 15 FOXP3 multi-organ autoimmune of these are the best phenomena including summarized in outcome. RIC References: enteropathy, chronic Table 5 of may be pre- D’Hennezel et al dermatitis, endocrinopathy, Barzaghi et al ferred.E69,E70 (2012),E66 hepatitis, nephritis and (2012).E67 At least Barzaghi et al (2012),E67 cytopenias.E66,E67 Patients do 2 additional cases Horino et al (2014),E68 not survive long-term without have been Burroughs et al (2007),E69 BMT. reported.E68,E69 Burroughs et al (2010)E70

Defects in Innate Immunity; Receptors & Signaling Components NF Kappa B Mutations in the nuclear Orange et al At least 1 Due to limited Essential Modulator factor-κB essential (2004)E71 estimate patient with experience, (NEMO) modulator (NEMO) gene, a incidence to be NEMO has comment on member of the nuclear 1:250,000 live male undergone HCT is likely Mutation: factor kB (NF-kB) births. Seven successful HCT premature. NEMO (IKBKG) pathway, impair NF-kB pateints,E71 1 (personal function, and generally patientE72 and 1 communication References: induce broad susceptibility patientE73 have been reported in Orange et al (2004),E71 to bacteria, viruses, and described. Orange et al Braue et al (2015),E72 fungi. Immunologic (2004) E71). Nishikomori (2004)E73 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. Complement Deficiencies C1q Deficiency Complement protein C1q is Globally, about 60 HCT has been HCT may be the recognition molecule of cases of C1q attempted in 3 clinically Mutation: the classical pathway, and deficiency have been C1q deficient beneficial. C1QA performs a diverse range of published.E75 In a patients, with complement and non- report of 45 patients improvement of References: complement functions. from 31 families, 36 clinical Kouser et l (2015),E74 Ligands derived from self, (80%) suffered from symptoms and van Schaarenburg et al non-self, and altered self are SLE of which 16 restoration of C1q (2015),E75 bound, and it can modulate the (36%) had SLE and production.E75,E76 Arkwright et al (2014)E76 functions of immune and non- infections, 5 (11%) immune cells including had infections only dendritic cells and and 4 (9%) had no microglia.E74 C1q may be symptoms.E75 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. Other Well-Defined Immuno-deficiencies

40 ADA-2 (Deficiency of LOF mutations in CECR1 are Nine (9) patients are Two HCT For both Adenosine Deaminase- associated with vascular and described.E77 procedures patients, 2); CECR1 LOF (Cat inflammatory changes.E77,E78 reported, both vasculopathy Eye Syndrome Patients experience patients are appears to have Chromosome Region, intermittent fevers, early onset surviving as of resolved Candidate 1) stroke and vasculopathy. July 2015.E79,E80 following HCT.

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 PGM3 deficiency PGM-3 affects multiple Three (3) patients HCT procedures HCT appears (phospho-glucomutase glycosylation pathways; from 3 families,E81 and resulted in promising. 3) AR Hypomorphic PGM-3 deficiency is an AR 8 patients from 2 correction of Mutations genetic syndrome of severe families,E82 and 9 neutropenia and atopy, increased serum IgE patients from 2 lymphopenia in 2 Mutation: levels, immune deficiency, families in TunisiaE83 patients.E81 PGM3 autoimmunity, and motor and have been reported. neurocognitive impairment. References: (Hyper IgE syndrome (HIES) Stray-Pedersen et al with neurological (2014),E81 impairment). The Zhang et al (2014)E82 immunologic mechanism of Sassi et al (2014),E83 the link between glycosylation abnormalities and immune dysregulation is not yet understood. Cartilage Hair CHH is a highly pleiotropic A study of 108 HCT has been HCT may be Hypoplasia (CHH) AR disorder caused by Finnish patients with described for 6 indicated for the (McKusick Type mutations in the ribonuclease CHH has been patients, all of immunologic Metaphyseal mitochondrial RNA published.E85 whom survived at complications of Chondrodysplasia) processing (RMRP) gene, and Immunologic features a median of 7 CHH. characterized by short-limbed of 12 patients have years post- Mutation: dwarfism due to skeletal been described.E84 transplant, with RMRP dysplasia; some patients may clinical and be predisposed to immunologic References: malignancies. Immunologic improvement.E84 Kavadas et al (2008)E84 findings are variable, and may Indications for Mäkitie et al (1993),E85 include CID, decreased T-cells HCT included with CD8 lymphopenia, and Omenn syndrome decreased mitogenic (4 patients) and responses.E84 Mortality from CID (2 patients). infections early in childhood may occur. Dyskeratosis Congenita DKC is a disorder of poor Estimated annual HCT outcomes Allogeneic HCT (DKC); X-linked telomere maintenance, due to incidence is less than have been is the only DKC1; AD TERC, a number of gene mutations 1:1,000,000.E87 described for 34 curative TERT, or TINF2; AR that lead to impaired patients.E88 treatment for the NOP10, NHP2, or ribosomal function.E86 Survival was associated bone TCAB1 Phenotypically patients have a 30%, 14 patients marrow failure. triad of abnormal skin were alive at last Mutations: pigmentation, nail dystrophy follow-up. DKC1 accounts for and leukoplakia of the Transplantation 40% of cases; TERT, oral mucosa. About 90% have from MSD using TERC, TINF2, NOP10, peripheral cytopenia of one or cyclo- NHP2, TCAB1 and more lineages, and at least phosphamide

41 CI6orf57 account for 70% of deaths are related to non-radiation 20% of cases; 40% are bleeding and opportunistic containing unidentified infections resulting from bone regimens was marrow failure. associated with References: low early Townsley et al (2014)E86 toxicity. Fernandez Garcia et al Pulmonary (2014),E87 complications Gadalla et al (2013),E88 and underlying disease contributed to late mortality. 1031 1032 Abbreviations: AD, autosomal dominant; AR, autosomal recessive; BCG, Bacille Calmette-Guerin; CID, combined 1033 immunodeficiency; CLL, chronic lymphocytic leukemia; CVID, common variable immune deficiency; GOF, gain of 1034 function; HLH, hemophagocytic lymphohistiocytosis; LOF, loss of function; MAC, myeloablative conditioning; 1035 MDS, myelodysplastic syndrome; MHC, major histocompatibility complex; NFkB, nuclear factor kB; NK, natural 1036 killer; OS, overall survival; PD, partial dominant; PjP, Pneumocystis jivrovecii pneumonia; RIC, reduced intensity 1037 conditioning; WT, wild type, XLP, X-linked lymphoproliferative syndrome. 1038 1039

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