TRANSPLANTATION OUTCOMES FOR

SEVERE COMBINED
IMMUNODEFICIENCY, 20002009

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ORIGINAL ARTICLE
Severe Combined Immunodeficiency
(SCID)
Primary Immunodeficiency disorder
Genetically heterogeneous and lethal disorder
of infancy.
Characteristics*
Severe T-cell lymphocytopenia
Lack of antigen-specific T-cell and B-cell immune
responses.
* Al-Herz et al. Primary immunodeficiency diseases: an update on the classification from
the International Union of Immunological Societies expert committee for primary
immunodeficiency. Front Immunol 2011; 2:54.
Severe Combined Immunodeficiency
(SCID)
Allogeneic BMT
HLA-identical sibling donor
Matched unrelated donor
Stem cells transplantation (from T-cell
depleted marrow or peripheral blood)
Haploidentical related donor
Umbilical cord blood
Background
The Primary Immune Deficiency Treatment
Consortium of North America was formed to
analyze the results of hematopoietic-cell
transplantation in children with severe combined
immunodeficiency (SCID) and other primary
immunodeficiencies.
Factors associated with a good transplantation
outcome needed to be identified in order to design
safer and more effective curative therapy,
particularly for children with SCID diagnosed at
birth.
Study Overview
Type of study:
Retrospective outcome analysis
Duration of Analysis:
2000 through 2009
Collaborating Clinics:
25 centers treating children with severe combined
immunodeficiency (SCID)
Materials and Methods
Inclusion criteria:
Total reviewed: 285 cases (240 infants with
classic SCID were included)
Absolute T-cell count of <300 per cubic
millimeter
Absence of T-cell responses to mitogens
Materials and Methods
Inclusion criteria:
B cells
B+ve >400 per cubic millimeter)
B-low 50 to 400 per cubic millimeter
Bve <50 per cubic millimeter
NK Cells
NK+ve >100 per cubic millimeter
NK-low 40 to 100 per cubic millimeter
NKve <40 per cubic millimeter
Materials and Methods
Measures of interest
Age at Transplantation
Infection
Conditioning regimen
Donor type
HLA match
Cell source
T cell depletion method
GVHD prophylaxis
Materials and Methods
Categories of conditioning regimen
1. None
2. Immunosuppression (fludarabine, cyclophosphamide,
antithymocyte globulin, or alemtuzumab)
3. Reduced intensity conditioning (regimens containing
melphalan, anti-CD45 antibodies, 200 to 400 cGy of
total-body irradiation, or busulfan administered at a
total dose of <12 mg per kilogram of body weight)
4. Myeloablative conditioning (regimens containing
busulfan at a total dose 12 mg per kilogram)
Materials and Methods
Immune Reconstitution
Evaluated at 100 days, 6 months, 1, 2 to 5, and
6 to 10 years after transplantation
Lymphocyte subset analysis
Proliferative response to PHA
IgG, IgA, and IgM levels
Treatment with IVIG
Chimerism
Materials and Methods
Immune Reconstitution
T-cell immune reconstitution
CD3+ count > 1000 per cubic millimeter
CD4+ count > 500 per cubic millimeter
Proliferation response of greater than 50
(M2/M1)
B-cell reconstitution
IgA recovery
Independence from IVIG treatment

Results
Cumulative Incidence of a Second Transplantation and Incidence of Acute
Graft-versus-Host Disease (GVHD) in 240 Infants with Severe Combined
Immunodeficiency.
Pai S-Y et al. N Engl J Med 2014;371:434-446
Cumulative Incidence of a Second Transplantation and Incidence of Acute
Graft-versus-Host Disease (GVHD) in 240 Infants with Severe Combined
Immunodeficiency.
Pai S-Y et al. N Engl J Med 2014;371:434-446
Cumulative Incidence of a Second Transplantation and Incidence of Acute
Graft-versus-Host Disease (GVHD) in 240 Infants with Severe Combined
Immunodeficiency.
Pai S-Y et al. N Engl J Med 2014;371:434-446
Grades of GVHD
Pai S-Y et al. N Engl J Med 2014;371:434-446
Cumulative Incidence of chronic Graft-versus-Host Disease (GVHD) and
relation of age at transplantation with infection in 240 Infants with Severe
Combined Immunodeficiency.
Pai S-Y et al. N Engl J Med 2014;371:434-446
Cumulative Incidence of chronic Graft-versus-Host Disease (GVHD) and
relation of age at transplantation with infection in 240 Infants with Severe
Combined Immunodeficiency.
Pai S-Y et al. N Engl J Med 2014;371:434-446
Cumulative Incidence of chronic Graft-versus-Host Disease (GVHD) and
relation of age at transplantation with infection in 240 Infants with Severe
Combined Immunodeficiency.
Age < 3.5 months
Age > 3.5 months
No infection
Resolved infection
Active Infection
Pai S-Y et al. N Engl J Med 2014;371:434-446
Factors that significantly affected survival in 240 Infants with Severe
Combined Immunodeficiency.
Pai S-Y et al. N Engl J Med 2014;371:434-446
Factors that significantly affected survival in 240 Infants with Severe
Combined Immunodeficiency.
Pai S-Y et al. N Engl J Med 2014;371:434-446
Factors that significantly affected survival in 240 Infants with Severe
Combined Immunodeficiency.
Characteristics of the Infants.
Pai S-Y et al. N Engl J Med
2014;371:434-446
Pai S-Y et al. N Engl J Med
2014;371:434-446
Characteristics of the Infants.
B+ 54%
B low 13%
B- 27%
Pai S-Y et al. N Engl J Med
2014;371:434-446
Characteristics of the Infants.
Pai S-Y et al. N Engl J Med
2014;371:434-446
Characteristics of the Infants.
Donor and Transplant Characteristics.
Pai S-Y et al. N Engl J Med 2014;371:434-446
Pai S-Y et al. N Engl J Med 2014;371:434-446
Donor and Transplant Characteristics.
Pai S-Y et al. N Engl J Med 2014;371:434-446
Donor and Transplant Characteristics.
Transplantation Complications and Outcomes.
Pai S-Y et al. N Engl J Med 2014;371:434-
446
Pai S-Y et al. N Engl J Med 2014;371:434-
446
Transplantation Complications and Outcomes.
Results of Multivariate Analysis of Outcomes and Contributing Factors.
Pai S-Y et al. N Engl J Med 2014;371:434-446
Pai S-Y et al. N Engl J Med 2014;371:434-446
Results of Multivariate Analysis of Outcomes and Contributing Factors.
Conclusions
Transplants from donors other than matched
siblings were associated with excellent survival
among infants with SCID identified before the
onset of infection.
All available graft sources are expected to lead to
excellent survival among asymptomatic infants.
Conclusions (1)
MMRD recipients have the highest probability
of a second transplant requirement
Acute GVHD affected 24% of all transplants
irrespective of donor type
UCB transplant recipients were most likely to
develop chronic GVHD
Active infection alone reduced the chance of
transplant success by 50% irrespective of age

Conclusions (2)
UCB transplant recipients have the lowest
probability of survival
Age at transplantation < 3.5 months is a
positive prognostic factor for all donor types
except UCB
Active infection significantly reduced survival
outcome in UCB and MMRD recipients


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