Biological Samples for Blood Disorders

Recruiting at 5 trial locations

Overseen By Eleonora Gambineri, MD

Age: < 65

Sex: Any

Trial Phase: Academic

Sponsor: Meyer Children's Hospital IRCCS

Disqualifiers: HIV, Transplant, Self-resolving AICs, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

700 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the treatment for Inborn Error of Immunity?

The research highlights the use of next-generation sequencing (NGS) as a powerful tool for diagnosing inborn errors of immunity, which can lead to more accurate and timely treatment options. Although not directly about treatment effectiveness, identifying the genetic basis of these disorders can help tailor specific therapies, potentially improving outcomes. ^{1 2 3 4 5}

What safety data exists for treatments related to inborn errors of immunity?

Studies on COVID-19 vaccines in patients with inborn errors of immunity (IEI) showed no moderate or severe vaccine-related adverse events, indicating general safety. However, intravenous immunoglobulin (IVIg) treatments for IEI can have some adverse effects, though these are not specified in detail. ^{6 7 8 9 10}

How does the treatment for inborn errors of immunity differ from other treatments?

The treatment for inborn errors of immunity is unique because it involves using advanced genetic testing, like Next-Generation Sequencing (NGS), to identify specific genetic mutations causing the condition. This approach allows for a more precise diagnosis and personalized treatment plan, which is different from traditional methods that may not target the underlying genetic cause. ^{1 5 8 11 12}

What is the purpose of this trial?

The universe of Inborn errors of Immunity (IEI) is rapidly expanding: their clinical spectrum is not only characterised by infections but often includes haematological complications. Moreover, an increasing number of "IEI phenocopies" due to somatic mutations in specific cell types are progressively being unveiled and complicate the genetic plot of IEI, which are therefore not only caused by germline mutations. However, these aspects have never been studied by large prospective studies. This study aims to fill this gap by prospectively recruiting patients \<25 y/o with haematologic disorders that fall into one of the following 4 subgroups: autoimmune cytopenia (AICs), polyclonal lymphoproliferation (PL), monoclonal (malignant) lymphoproliferation (ML), bone marrow failure/myelodysplasia (BMF/MDS). Recruited subjects will undergo an extensive immunologic workup (extended immunophenotyping, cytokine and autoantibody dosage) together with genetic testing (NGS) to detect both germline and somatic variants. Bulk RNA sequencing will be performed either as functional validation of variants or to identify altered pathways in selected cases with inconclusive genetics. Patient advocacy organisations (PAOs) will be pivotal to assist patients' needs throughout the project and to raise awareness of predictive and yet unknown signs of IEI. The study involves recruitment a total of almost 700 children over a 3-year period. Considering recent studies on AICs and BMF/MDS, a global detection rate of 30% "hidden" IEI is expected, with higher rates in the AIC subgroup and lower ones for ML, given the complexity of lymphoma pathogenesis. New IEI candidate genes or new examples of IEI phenocopies are expected to be identified. The immunological workup should detect early disease biomarkers or currently unknown molecular signatures of specific disorders. These may increase the chance of identifying an IEI in a specific subgroup and promptly address the patient to a targeted treatment or to hematopoietic stem cell transplantation, avoiding late complications, increasing patients' survival, and abating the economic burden of the disease on healthcare services. Finally, involvement of PAOs may foster patients' knowledge about their condition, increasing their compliance to disease follow-up and treatment and ameliorating their quality of life.

Eligibility Criteria

This trial is for children under 25 years old with certain blood disorders, including autoimmune cytopenia, lymphoproliferation (both polyclonal and monoclonal), or bone marrow failure/myelodysplasia. Participants will undergo extensive immune system and genetic testing to uncover hidden immune defects.

Inclusion Criteria

I am younger than 25 years old.

Signed Informed Consent

I have been diagnosed with an autoimmune or blood disorder.

Exclusion Criteria

My lymphoma is due to HIV or after a transplant.

Patient with self-resolving or post-infective AICs

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Immunologic Workup

Participants undergo extensive immunologic workup including extended immunophenotyping, cytokine and autoantibody dosage, and genetic testing to detect germline and somatic variants.

12 weeks

Genetic Analysis

Bulk RNA sequencing is performed for functional validation of variants or to identify altered pathways in selected cases with inconclusive genetics.

8 weeks

Follow-up

Participants are monitored for safety and effectiveness after the initial workup and analysis, with involvement of patient advocacy organizations to assist with follow-up and treatment compliance.

6 months

Treatment Details

Interventions

• Inborn Error of Immunity

Trial Overview The study tests if detailed immunologic workup and genetic testing can reveal inborn errors of immunity behind common haematological diseases. It aims to identify early disease biomarkers or unknown molecular signatures that could lead to targeted treatments.

Participant Groups

Group I: Patients with Haematological Disorders Experimental Treatment 1 Intervention

Patients with diagnosed autoimmune cytopenias (AIC), polyclonal lymphoproliferation (PL), lymphoma (ML), bone marrow failure, and myelodysplastic syndrome (BMF/MDS)

Who Is Running the Clinical Trial?

Meyer Children's Hospital IRCCS

Lead Sponsor

Trials

62

Recruited

17,500+

Findings from Research

Next-Generation Sequencing (NGS) has been successfully implemented in Chandigarh, North India, allowing for the genetic diagnosis of Inborn Errors of Immunity (IEI) in 121 patients, with pathogenic variants identified in 77 of them.

The use of a targeted gene panel for IEI not only provided accurate diagnoses but also facilitated genetic counseling and access to appropriate treatments, highlighting the efficacy and cost-effectiveness of NGS in managing these complex disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Utility of targeted next generation sequencing for inborn errors of immunity at a tertiary care centre in North India. Rawat, A., Sharma, M., Vignesh, P., et al.[2022]

Hematopoietic stem cell transplantation (HSCT) is an effective curative treatment for pediatric patients with inborn errors of immunity (IEI), with a 1-year overall survival rate of 80% for identical donors, 72% for haploidentical donors, and 63% for cord blood donors.

The study involved 47 patients treated between 2007 and 2018, highlighting that early intervention and treatment in specialized centers can significantly improve survival outcomes for these children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hematopoietic Stem Cell Transplantation in Children with Inborn Errors of Immunity: a Multi-center Experience in Colombia. Olaya, M., Franco, A., Chaparro, M., et al.[2021]

In a study of 165 patients suspected of having inborn errors of immunity (IEI), next-generation sequencing (NGS) provided a definitive genetic diagnosis in 24.6% of pediatric patients and 9% of adults, highlighting its effectiveness in early diagnosis, especially in children.

The study found that when a definitive diagnosis was made, 76% of patients experienced a change in disease management, indicating that NGS not only aids in diagnosis but also significantly impacts treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Implementation of Early Next-Generation Sequencing for Inborn Errors of Immunity: A Prospective Observational Cohort Study of Diagnostic Yield and Clinical Implications in Dutch Genome Diagnostic Centers. Elsink, K., Huibers, MMH., Hollink, IHIM., et al.[2022]

Next-generation sequencing (NGS) is a crucial tool for diagnosing inborn errors of immunity (IEIs), as it can confirm known diseases and identify new genetic defects, enhancing our understanding of immune system disorders.

Understanding genetic terminology and NGS technologies is essential for clinical specialists, as this knowledge can lead to personalized treatment strategies and improved management of patients with IEIs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Next-generation sequencing for inborn errors of immunity. Lee, K., Abraham, RS.[2022]

Many patients with inborn errors of immunity experience long delays in diagnosis, which can hinder timely and appropriate treatment for their conditions.

The document provides a comprehensive guide for clinical immunologists, outlining key clinical features and available laboratory tests to facilitate quicker and more accurate diagnoses of immune dysfunction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Toolkit and Framework for Optimal Laboratory Evaluation of Individuals with Suspected Primary Immunodeficiency. Knight, V., Heimall, JR., Chong, H., et al.[2021]

This study provides whole-exome sequencing (WES) data from 20 Brazilian patients suspected of having inborn errors of immunity (IEI), which can help improve the diagnosis of these complex genetic disorders.

The analysis identified 116 rare pathogenic or likely pathogenic variants, highlighting the potential for WES to uncover genetic causes of IEI, although the study faced limitations due to insufficient clinical data and lack of functional studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessing whole-exome sequencing data from undiagnosed Brazilian patients to improve the diagnostic yield of inborn errors of immunity. Ferreira, CS., da Silva Francisco Junior, R., Gerber, AL., et al.[2023]

In a study of 363 patients with inborn errors of immunity receiving a total of 22,667 intravenous immunoglobulin (IVIg) infusions, 43.2% of patients experienced at least one adverse reaction, highlighting the need for careful monitoring during treatment.

The most common adverse effects included myalgia, chills, headache, fever, and hypotension, particularly occurring during the initial infusions, indicating that early infusions may pose a higher risk for adverse reactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse reactions in a large cohort of patients with inborn errors of immunity receiving intravenous immunoglobulin. Esmaeilzadeh, H., Askarisarvestani, A., Hosseini, N., et al.[2021]

COVID-19 vaccines, including Sputnik, AstraZeneca, Sinopharm, Moderna, and Pfizer, were found to be safe for patients with inborn errors of immunity (IEI) in Argentina, with no moderate or severe adverse events reported.

While the immune response in IEI patients was lower compared to healthy controls, the vaccines still elicited specific antibody responses and T cell immunity, particularly with the Moderna vaccine showing a stronger humoral response in pediatric patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

COVID-19 Vaccination Responses with Different Vaccine Platforms in Patients with Inborn Errors of Immunity. Erra, L., Uriarte, I., Colado, A., et al.[2023]

In a study of 342 patients with inborn errors of immunity (IEI) receiving mRNA COVID-19 vaccines, no serious adverse events like hospitalization or anaphylaxis were reported, indicating a reassuring safety profile for this population.

Most patients experienced mild local or systemic reactogenicity-related symptoms after vaccination, with fewer adverse events reported after booster doses, suggesting that the vaccines are well-tolerated even in individuals with immune deficiencies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of mRNA COVID-19 Vaccines in Patients with Inborn Errors of Immunity: an Italian Multicentric Study. Milito, C., Cinetto, F., Garzi, G., et al.[2023]

The traditional guidelines for newborn screening, established by Wilson and Jungner, are being reconsidered due to advancements in genomic technologies like next-generation sequencing, which could enhance early detection of diseases.

Inborn errors of immunity (IEI), a group of over 450 genetic disorders that can lead to severe health issues if not diagnosed early, should be included in newborn screening programs, alongside severe combined immunodeficiency, to improve outcomes through timely diagnosis and treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An appraisal of the Wilson & Jungner criteria in the context of genomic-based newborn screening for inborn errors of immunity. King, JR., Notarangelo, LD., Hammarström, L.[2023]

In California's newborn screening program for severe combined immunodeficiency (SCID), 993,724 infants were screened, identifying 50 with significant T-cell lymphopenia, which is crucial for early diagnosis and management of SCID and related conditions.

Among those identified, 15 infants required hematopoietic cell or thymus transplantation, with a high survival rate of 93%, demonstrating the efficacy of TREC testing in improving health outcomes for affected infants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Newborn screening for severe combined immunodeficiency and T-cell lymphopenia in California: results of the first 2 years. Kwan, A., Church, JA., Cowan, MJ., et al.[2021]

In a study of 313 patients with inborn errors of immunity (IEIs), 16.3% exhibited atopic manifestations, with food allergies and atopic dermatitis being the most common conditions.

Atopic dermatitis and food allergies were significantly more prevalent in patients with combined immunodeficiency (CID), suggesting that these atopic conditions may indicate an underlying IEI, particularly in CID cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Prevalence of Atopic Manifestations in 313 Iranian Patients with Inborn Errors of Immunity. Ghaini, M., Jamee, M., Mahdaviani, SA., et al.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

Utility of targeted next generation sequencing for inborn errors of immunity at a tertiary care centre in North India. [2022]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Hematopoietic Stem Cell Transplantation in Children with Inborn Errors of Immunity: a Multi-center Experience in Colombia. [2021]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Implementation of Early Next-Generation Sequencing for Inborn Errors of Immunity: A Prospective Observational Cohort Study of Diagnostic Yield and Clinical Implications in Dutch Genome Diagnostic Centers. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Next-generation sequencing for inborn errors of immunity. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

A Toolkit and Framework for Optimal Laboratory Evaluation of Individuals with Suspected Primary Immunodeficiency. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Assessing whole-exome sequencing data from undiagnosed Brazilian patients to improve the diagnostic yield of inborn errors of immunity. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

Adverse reactions in a large cohort of patients with inborn errors of immunity receiving intravenous immunoglobulin. [2021]

8. Netherlands pubmed.ncbi.nlm.nih.gov

COVID-19 Vaccination Responses with Different Vaccine Platforms in Patients with Inborn Errors of Immunity. [2023]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Safety of mRNA COVID-19 Vaccines in Patients with Inborn Errors of Immunity: an Italian Multicentric Study. [2023]

10. United States pubmed.ncbi.nlm.nih.gov

An appraisal of the Wilson & Jungner criteria in the context of genomic-based newborn screening for inborn errors of immunity. [2023]

11. United States pubmed.ncbi.nlm.nih.gov

Newborn screening for severe combined immunodeficiency and T-cell lymphopenia in California: results of the first 2 years. [2021]

12. Switzerland pubmed.ncbi.nlm.nih.gov

The Prevalence of Atopic Manifestations in 313 Iranian Patients with Inborn Errors of Immunity. [2021]