413 Early Hematopoietic Cell Transplant (HCT) Outcomes of Children with Severe Combined Immunodeficiency Disease (SCID): The First Seventy Four Patients of the Primary Immune Deficiency Treatment Consortium (PIDTC) Prospective Study 6901

Track: Poster Abstracts
Saturday, February 14, 2015, 6:45 PM-7:45 PM
Grand Hall CD (Manchester Grand Hyatt)
Jennifer Heimall, MD , Division of Allergy and Immunology, The Children's Hospital of Philadelphia, Philadelphia, PA
Brent R. Logan, PhD , Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI
Morton J Cowan, MD , Pediatric Allergy Immunology and Blood and Marrow Transplant Division, UCSF Benioff Children's Hospital, San Francisco, CA
Luigi D. Notarangelo, MD , Program on Primary Immunodeficiencies, Children’s Hospital Boston, Harvard Medical School, Boston, MA
Linda M Griffith, MD, PhD , DAIT, NIAID, NIH, Bethesda, MD
Jennifer Puck, MD , Pediatric Allergy Immunology and Blood and Marrow Transplant Division, UCSF Benioff Children's Hospital, San Francisco, CA
Suhag Parikh, MD , Pediatric BMT Program, Duke University Medical Center, Durham, NC
Richard J O'Reilly, MD , Memorial Sloan Kettering Cancer Center, NY, NY
Sung-Yun Pai, MD , Hematology-Oncology, Boston Children's Hospital, Boston, MA
Imelda C Hanson, MD , Immunology, Allergy and Rheumatology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX
Caridad Martinez, MD , Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, Houston, TX
Michael A. Pulsipher, MD , Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT
Neena Kapoor, MD , Division of Hematology, Oncology and Blood & Marrow Transplantation, Children's Hospital Los Angeles, Los Angeles, CA
Frederick Goldman, MD , Department of Pediatrics, The University of Alabama at Birmingham, Birmingham, AL
Morris Kletzel, MD, FAAP, MBA , Northwestern University Feinberg School of Medicine, Chicago, IL
Lisa Filipovich, MD , Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
Geoff Cuvellier, MD , CC Manitoba, Manitoba, MB, Canada
Monica Thakar, MD , Pediatric Hematology-Oncology-Transplant, Medical College of Wisconsin, Milwaukee, WI
Lauri Burroughs, MD , Fred Hutchinson Cancer Research Center, Seattle, WA
Alan Knudsen, MD , St Louis University, St. Louis, MO
James A Connelly, MD , Pediatric Blood and Marrow Transplant Program, University of Michigan, Ann Arbor, MI
Troy C Quigg, DO, MS , Pediatric Blood and Marrow Stem Cell Transplant, Texas Transplant Institute, San Antonio, TX
Angela R. Smith, MD, MS , Pediatric Hematology/Oncology/Blood and Marrow Transplantation, University of Minnesota Medical Center, Fairview, Minneapolis, MN
Kathleen Sullivan, MD, PhD , The Children's Hospital of Philadelphia, Philadelphia, PA
Brett J. Loechelt, MD , Children's National Medical Center, Washington, DC
Alfred P. Gillio, MD , Institute for Pediatric Cancer and Blood Disorders, Hackensack University Medical Center, Hackensack, NJ
Elie Haddad, MD PhD , Paediatric Immunology, Ste-Justine Hospital, Montreal, QC, Canada
Donald B. Kohn, MD , Division of Hematology/Oncology, Mattel Children's Hospital, University of California, Los Angeles, Los Angeles, CA
Thomas Fleisher, MD , Laboratory of Host Defenses, National Institutes of Health, Bethesda, MD
William Shearer, MD, PhD , Immunology, Allergy and Rheumatology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX
Christopher C. Dvorak, MD , University of San Francisco, San Francisco, CA
Rebecca H Buckley, MD , Duke University Medical Center, Durham, NC
Presentation recording not available for download or distribution as requested by the presenting author.

We report interim evaluation of the 1st 74 patients who underwent HCT on Protocol 6901, a natural history study to identify variables associated with overall survival (OS) & immune reconstitution in SCID. From 8/2010 – 5/2013, patients from 21 centers underwent diagnostic work-up & therapy according to local practice (Table 1). Consenting patients were centrally reviewed & assigned to typical SCID or leaky SCID/Omenn Syndrome, or Reticular Dysgenesis (RD).

Survivors had at least 1y follow up. OS at 1y was 88% (63/74). Grade 2-4 aGVHD was seen in 19%, Grade 3-4 aGVHD in 8% & cGVHD in 17% by 1y. A 2nd HCT was needed in 6 patients by 1y. Of these, 5/6 survived. Initially 5 received no conditioning/serotherapy vs. 1 who received RIC/MAC (p = 0.005).

Leaky SCID/Omenn had similar 1y OS to typical SCID (86% vs. 92%; p = 0.212; Fig 1). Both patients with RD died.  By donor type 1y OS was 100% for MRD; 94% for MMRD; 84% for URD & 73% for UCB. Mortality was similar irrespective of conditioning: 13% no conditioning/serotherapy; 18% RIC; 15% MAC.  Mortality was due to infection [CMV (3), EBV PTLD (1), RSV/PCP (1), Trichosporon (1) & Enterococcus (1)] and, seen only in MAC, HCT complications [VOD (3), encephalopathy (1)].

At 1y, median CD3 chimerism was >98% regardless of conditioning. Use of RIC/MAC vs no conditioning/serotherapy was associated with better median lineage specific donor chimerism in CD19 (99% vs 10%; p = 0.005) & myeloid cells (97% vs 1%; p <0.001) & trended toward freedom from IVIG (43% vs. 17%; p = 0.056). In typical SCID median CD4 counts were higher in those receiving RIC/MAC (1482 vs 878; p = 0.022; Fig 2). In cohort-wide comparison of HCT with vs without conditioning, median CD4 count (1345 vs 855), %CD45RA (43 vs. 40) & PHA response (both 100%) were not significantly different.

Survival of patients with typical SCID & leaky SCID/Omenn after HCT was high, but problems remained. Deaths were most commonly related to infection, but a 3rd were attributable to conditioning toxicities, in particular VOD with MAC.  This emphasizes need to minimize busulfan use. Conditioning improved certain aspects of immune reconstitution at 1y & decreased need for 2nd HCT. GVHD affected ~1 in 5 infants. Future efforts to decrease GVHD & establish safer chemotherapy exposure in very young infants requiring conditioning are needed to improve outcomes. Longer-term follow-up of these patients will identify factors that impact late effects & quality of life post HCT for SCID.

Supported by NIH-NIAID & ORDR/NCATS, Grant #U54AI082973


Table 1: Clinical Characteristics

Typical (n=51)

Leaky, Omenn, RD (n=23)

Age at Dx (days)

27

52

Age at HCT (days)

101 (16-461)

145 (30-5137)

Genotype

ADA

2

0

AK2

0

2

Artemis

0

2

CD3d

3

0

IL2Rg

26

2

IL7R

5

0

JAK3

3

1

RAG 1, 2

7

11

RMRP

0

1

Zap70

0

1

Unknown

5

3

Donor

MRD

8

3

MMRD

16

1

Adult URD

12

13

UCB

16

6

Conditioning

None

17

1

Serotherapy-only

5

1

RIC

7

10

MAC (Bu > 8 mg/kg)

22

11

GVHD Prophylaxis

None

5

0

TCD

18

2

CI Only

3

2

CI + Other

25

19

Fig 1

Fig 2

Disclosures:
K. Sullivan, Baxter, grant recipient: Research Funding
Immune deficiency foundation, consultant: Consultancy

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