Prospective Newborn Screening for SCID in Germany: A First Analysis by the Pediatric Immunology Working Group (API).

BACKGR OUND: T-cell receptor excision circle (TREC)-based newborn screening (NBS) for severe combined immunodeficiencies (SCID) was introduced in Germany in August 2019. METHODS: Children with abnormal TREC-NBS were referred to a newly established network of Combined Immunodeficiency (CID) Clinics and Centers. The Working Group for Pediatric Immunology (API) and German Society for Newborn Screening (DGNS) performed 6-monthly surveys to assess the TREC-NBS process after 2.5 years. RESULTS: Among 1.9 million screened newborns, 88 patients with congenital T-cell lymphocytopenia were identified (25 SCID, 17 leaky SCID/Omenn syndrome (OS)/idiopathic T-cell lymphocytopenia, and 46 syndromic disorders). A genetic diagnosis was established in 88%. Twenty-six patients underwent hematopoietic stem cell transplantation (HSCT), 23/26 within 4 months of life. Of these, 25/26 (96%) were alive at last follow-up. Two patients presented with in utero onset OS and died after birth. Five patients with syndromic disorders underwent thymus transplantation. Eight syndromic patients deceased, all from non-immunological complications. TREC-NBS missed one patient, who later presented clinically, and one tracking failure occurred after an inconclusive screening result. CONCLUSION: The German TREC-NBS represents the largest European SCID screening at this point. The incidence of SCID/leaky SCID/OS in Germany is approximately 1:54,000, very similar to previous observations from North American and European regions and countries where TREC-NBS was implemented. The newly founded API-CID network facilitates tracking and treatment of identified patients. Short-term HSCT outcome was excellent, but NBS and transplant registries will remain essential to evaluate the long-term outcome and to compare results across the rising numbers of TREC-NBS programs across Europe.

International Recommendations for the Diagnosis and Management of Patients With Adrenoleukodystrophy: A Consensus-Based Approach.

Pathogenic variants in the ABCD1 gene cause adrenoleukodystrophy (ALD), a progressive metabolic disorder characterized by 3 core clinical syndromes: a slowly progressive myeloneuropathy, a rapidly progressive inflammatory leukodystrophy (cerebral ALD), and primary adrenal insufficiency. These syndromes are not present in all individuals and are not related to genotype. Cerebral ALD and adrenal insufficiency require early detection and intervention and warrant clinical surveillance because of variable penetrance and age at onset. Newborn screening has increased the number of presymptomatic individuals under observation, but clinical surveillance protocols vary. We used a consensus-based modified Delphi approach among 28 international ALD experts to develop best-practice recommendations for diagnosis, clinical surveillance, and treatment of patients with ALD. We identified 39 discrete areas of consensus. Regular monitoring to detect the onset of adrenal failure and conversion to cerebral ALD is recommended in all male patients. Hematopoietic cell transplant (HCT) is the treatment of choice for cerebral ALD. This guideline addresses a clinical need in the ALD community worldwide as the number of overall diagnoses and presymptomatic individuals is increasing because of newborn screening and greater availability of next-generation sequencing. The poor ability to predict the disease course informs current monitoring intervals but remains subject to change as more data emerge. This knowledge gap should direct future research and illustrates once again that international collaboration among physicians, researchers, and patients is essential to improving care.

Adoptive transfer of ex vivo expanded regulatory T cells improves immune cell engraftment and therapy-refractory chronic GvHD.

Graft-versus-host disease (GvHD) is still the major non-relapse, life-limiting complication after hematopoietic stem cell transplantation. Modern pharmacologic immunosuppression is often insufficient and associated with significant side effects. Novel treatment strategies now include adoptive transfer of ex vivo expanded regulatory T cells (Tregs), but their efficacy in chronic GvHD is unknown. We treated three children suffering from severe, therapy-refractory GvHD with polyclonally expanded Tregs generated from the original stem cell donor. Third-line maintenance immunosuppression was tapered to cyclosporin A and low-dose steroids shortly before cell transfer. Regular follow-up included an assessment of the subjective and objective clinical development, safety parameters, and in-depth immune monitoring. All patients showed marked clinical improvement with substantially decreased GvHD activity. Laboratory follow-up showed a significant enhancement of the immunologic engraftment, including lymphocytes and dendritic cells. Monitoring the fate of Tregs by next-generation sequencing demonstrated clonal expansion. In summary, adoptive transfer of Tregs was well tolerated and able to modulate an established undesired T cell mediated allo-response. Although no signs of overimmunosuppression were detectable, the treatment of patients with invasive opportunistic infections should be undertaken with caution. Further controlled studies are necessary to confirm these encouraging effects and eventually pave the way for adoptive Treg therapy in chronic GvHD.

Total Body Irradiation (TBI) using Helical Tomotherapy in children and young adults undergoing stem cell transplantation.

BACKGROUND: Establishing Total Body Irradiation (TBI) using Helical Tomotherapy (HT) to gain better control over dose distribution and homogeneity and to individually spare organs at risk. Because of their limited body length the technique seems especially eligible in juvenile patients. PATIENTS AND METHODS: The cohort consisted of 10 patients, 6 female and 4 male, aged 4 - 22 y with acute lymphoblastic- (ALL) or acute myeloic leukemia (AML). All patients presented with high risk disease features. Body length in treatment position ranged from 110-180 cm. Two Gy single dose was applied BID to a total dose of 12 Gy. Dose volume constraint for the PTV was 95% dose coverage for 95% of the volume. The lungs were spared to a mean dose of [less than or equal to] 10 Gy. Patients were positioned in a vac-loc bag in supine position with a 3-point head mask. RESULTS: Average D95 to the PTV was 11.7 Gy corresponding to a mean coverage of the PTV of 97.5%. Dmean for the lungs was 9.14 Gy. Grade 3-4 side effects were not observed. CONCLUSIONS: TBI using HT is feasible and well tolerated. A benefit could be demonstrated with regard to dose distribution and homogeneity and the selective dose-reduction to organs at risk.