Unresolved issues in hematopoietic stem cell transplantation for severe combined immunodeficiency: Need for safer conditioning and reduced late effects

Abstract

In this review we discuss recent outcomes of hematopoietic cell transplantation (HCT) for patients with severe combined immunodeficiency (SCID), including survival, T- and B-cell reconstitution, and late effects, particularly those related to genotype, use of conditioning regimen, and use of alternative donors. We identify the following issues that require additional data, which can be obtained through cooperative studies: outcomes of patients with SCID who did not receive conditioning before alternative donor HCT; outcomes of patients with SCID who did not receive graft-versus-host disease prophylaxis after T cell–replete HCT; late effects of HCT for patients with SCID, including neurocognitive outcomes, growth, and development; and their relationship to genotype and use of alkylating agents for conditioning. Careful follow-up of outcomes of all newborns receiving diagnoses based on newborn screening programs for SCID is essential because data are scarce on the effects of conditioning regimens in very young patients. A consensus on the definition of T- and B-cell recovery, criteria for additional “boosts,” pharmacokinetic data of chemotherapy agents used in young children, and uniformity of the use of various chemotherapy agents are needed to compare results among institutions. Finally, development of new nontoxic conditioning regimens for HCT that can be safely used in very young children is required.

Severe Combined Immunodeficiency Disorders

“…In addition, providers who perform hematopoietic stem cell transplant must be made aware of increased sensitivity of tissues to DNA cross-linking medications and adjust any conditioning regimens accordingly. 62,63 For example, use of alkylator therapy in Artemis deficiency should be avoided because it is associated with poor growth, abnormal dental development, and late endocrinopathies. 64 In summary, although patients with SCID do not need to be treated delicately, they should be managed closely and carefully.…”

“…As a result, many controversial issues exist regarding optimal transplant methods. 63,78 The most controversial issue surrounds the use or absence of conditioning for haploidentical or HLA-matched unrelated donor transplant in terms of effects on B-cell function, NK-cell function, and late complications. In terms of B cells, reconstitution using parental donor bone marrow cells without conditioning (but with rigorous Tcell depletion) has been reported, but efficacy varies by molecular defect.…”

“…With the use of conditioning, problems after 2 years posttransplant include death from GVHD (7%), chronic GVHD (10%), secondary malignancies and lymphoproliferative disease (2%-3%), need for long-term nutritional support (20%), human papillomavirus infections (25%), autoimmune or inflammatory complications (13%), and cognitive difficulties. 63 The risk for neuropsychiatric problems after use of chemotherapeutic agents remains acknowledged 87,88 and closely observed with recognition of the fact that ADA-, 89 Cernunnos-, and DNA ligase IVdeficient patients develop neurocognitive deficits because the molecular defects affect central nervous system tissues in manners that cannot be corrected by hematopoietic stem cell transplant. With use of rigorous T-cell depletion and no conditioning, late effects include minimal (<5%) prevalence of cutaneous GVHD, autoimmune disease, thyroid disease, seizure disorder, and cerebral palsy.…”

Primary immunodeficiencies: a decade of shifting paradigms, the current status and the emergence of cutting-edge therapies and diagnostics

“…In spite of the development of various therapeutic modalities, HSCT remains the mainstay therapy for various lifethreatening PIDs including SCID [86]. With advances made in terms of HLA typing, development of safer and less-toxic conditioning regimen, supportive care, as well as more effective antiviral and antifungal agents, the outcome of HSCT has significantly improved [86], resulting in 90% success rate in patients with optimum physical condition and with a wellmatched family donor [87,88].…”

Device and application development for haematopoietic stem and progenitor cell (HSPC) and mesenchymal stromal cell (MSC) 3D spheroid cultures

“…age and other underlying medical conditions), and the characteristics of the available graft. In some cases, HSCT can be performed without a conditioning regimen, for example, in children with severe combined immunodeficiency (SCID) disease, who have a T cell deficiency [25].…”