Immune reconstitution and survival of 100 SCID patients post–hematopoietic cell transplant: a PIDTC natural history study

Abstract

• Active infection pretransplant adversely impacts survival (81% in patients with active infection vs 95% in infectionfree patients; P 5 .009).• Preparative chemotherapy improved 1-year post-HCT median CD4 counts (P 5 .02) and freedom from IV immunoglobulin (P , .001).The Primary Immune Deficiency Treatment Consortium (PIDTC) is enrolling children with severe combined immunodeficiency (SCID) to a prospective natural history study. We analyzed patients treated with allogeneic hematopoietic cell transplantation (HCT) from 2010 to 2014, including 68 patients with typical SCID and 32 with leaky SCID, Omenn syndrome, or reticular dysgenesis. Most (59%) patients were diagnosed by newborn screening or family history. The 2-year overall survival was 90%, but was 95% for those who were infection-free at HCT vs 81% for those with active infection (P 5 .009). Other factors, including the diagnosis of typical vs leaky SCID/Omenn syndrome, diagnosis via family history or newborn screening, use of preparative chemotherapy, or the type of donor used, did not impact survival. Although 1-year post-HCT median CD4 counts and freedom from IV immunoglobulin were improved after the use of preparative chemotherapy, other immunologic reconstitution parameters were not affected, and the potential for late sequelae in extremely young infants requires additional evaluation. After a T-cell-replete graft, landmark analysis at day 1100 post-HCT revealed that CD3 < 300 cells/mL, CD8 < 50 cells/mL, CD45RA < 10%, or a restricted Vb T-cell receptor repertoire (<13 of 24 families) were associated with the need for a second HCT or death. In the modern era, active infection continues to pose the greatest threat to survival for SCID patients. Although newborn screening has been effective in diagnosing SCID patients early in life, there is an urgent need to identify validated approaches through prospective trials to ensure that patients proceed to HCT infection free. The trial was registered at www.clinicaltrials.gov as #NCT01186913. (Blood. 2017;130(25):2718-2727

Newborn screening for severe combined immunodeficiency and T‐cell lymphopenia

“…Haplo‐identical parental bone marrow or mobilized peripheral blood hematopoietic stem cells (PBSC) depleted of T cells have been used, as well as closely matched bone marrow, PBSCs, or cord blood from unrelated donors. In addition, enzyme replacement therapy (ERT) is available for adenosine deaminase (ADA) deficient SCID, and autologous hematopoietic cell correction by gene therapy (GT) has been successful for ADA deficient and X‐linked SCID, with Artemis‐deficient SCID also being tested in a clinical trial . Best outcomes are achieved if infants are treated early to avoid infectious complications, as documented by single center reports and by retrospective and prospective multicenter studies from the Immune Deficiency Foundation and Primary Immune Deficiency Treatment Consortium (PIDTC) …”

Mini Review: Screening and Management of Late Effects in Patients with Severe Combined Immunodeficiency after Allogeneic Hematopoietic Cell Transplantation

“…The first successful hematopoietic cell transplantation (HCT) for SCID was performed in 1968, and allogeneic HCT remains the standard of care for SCID today. Outcomes are greatly improved with early transplantation in the first 3.5 months of life and particularly before onset of infection, with reported survival rates of 80% to 95% regardless of donor source or conditioning [1][2][3][4][5][6][7][8] . Newborn screening for SCID was first initiated in Wisconsin in 2008, and today, 93% of all newborns in the US receive SCID screening 9,10 .…”

“…T cell spectratyping is recommended to evaluate diversity of the T cell repertoire 20 , where a skewed repertoire may be associated with a high risk of infection and autoimmunity. A restricted Vβ T-cell receptor repertoire was also recently shown to be associated with need for second transplant and death 8 . Measurement of lineage-specific engraftment is also imperative, as autologous T cell re-emergence in the setting of graft failure may be missed by standard T cell flow cytometry, particularly in those with hypomorphic SCID.…”

“…B-SCID genotypes, active infection at time of HCT, and graft-versus-host disease (GVHD) are all associated with poor T cell recovery 3,7,8,17 . Evaluation of T cell reconstitution should include enumeration of T cell populations (i.e., CD3, CD4 and CD8 T cell counts), naïve (CD4+CD45RA+) T cells and/or recent thymic emigrants (CD4+/CD45RA+/CD31+), and T cell function via proliferation to mitogens and/or anti-CD3.…”

“…The use of conditioning before HCT for SCID remains controversial and varies by transplant center, donor type, clinical presentation, and SCID genotype. Preparative conditioning has been associated with greater likelihood of myeloid engraftment, long-term T cell reconstitution, and freedom from immunoglobulin replacement 7,8,[11][12][13][14] . However, the long-term consequences of using chemotherapeutic agents in early infancy remain incompletely understood.…”