Refractory immune thrombocytopenia successfully treated with bortezomib in a child with 22q11.2 deletion syndrome, complicated by Evans syndrome and hypogammaglobulinemia

Conti, Francesca; Gottardi, Francesca; Moratti, Mattia; Belotti, Tamara; Ferrari, Simona; Selva, Paola; Bassi, M.; Zama, Daniele; Pession, Andrea

doi:10.1080/09537104.2021.2002835

Cited by 9 publications

(5 citation statements)

References 15 publications

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“…The immune dysregulation manifestations described in DGS include impaired antibody immune response resulting in poor response to vaccines and IgA deficiency (12-14). Autoimmune diseases such as juvenile rheumatoid arthritis, ITP, autoimmune hemolytic anemia, and Hashimoto thyroiditis are collectively common in DGS patients (14)(15)(16)(17). The patient in the present study was shown to have an ALPS-like phenotype in many aspects, including decreased Tregs, increased IL-10 levels, and elevated DNT cells (6).…”

Section: Discussionmentioning

confidence: 47%

Case report: Effectiveness of sirolimus in treating partial DiGeorge Syndrome with Autoimmune Lymphoproliferative Syndrome (ALPS)-like features

Mou

Chen

et al. 2023

Front. Pediatr.

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BackgroundDiGeorge Syndrome (DGS) is a rare disease associated with 22q11.2 chromosomal microdeletion, also known as a velocardiofacial syndrome, based on the frequent involvements of the palate, facial, and heart problems. Hematologic autoimmunity is rare in DGS but presents with a refractory course and poor prognosis. Herein, we report a case of partial DGS in a patient with refractory immune cytopenia and autoimmune lymphoproliferative syndrome (ALPS)-like manifestations.Case descriptionA 10-year-old boy with growth retardation presented initially with a ventricular septal defect at 7 months old, which had been repaired soon after. The patient suffered from thrombocytopenia and progressed into chronic refractory immune thrombocytopenia (ITP) at 30 months old. One year later, the patient developed multilineage cytopenias including thrombocytopenia, neutropenia, and anemia. First-line treatment of ITP, like high-dose dexamethasone and intravenous immunoglobulin, had little or short-term effect on controlling symptoms. Whole-exome sequencing revealed the presence of a de novo heterozygous 2.520 Mb deletion on chromosome 22q11.21. Moreover, decreased proportion of naive T cells and elevated double-negative T cells were found. The patient was given sirolimus therapy (1.5 mg/m2, actual blood concentration range: 4.0–5.2 ng/ml) without adding other immunosuppressive agents. The whole blood cell count was gradually restored after a month, and the disease severity was soothed with less frequency of infections and bleeding events. Decreased spleen size and restrained lymph node expansion were achieved after 3-month sirolimus monotherapy.ConclusionsThis case is the first description on the efficacy of sirolimus monotherapy to treat refractory multilineage cytopenias of DGS presented with ALPS-like features.

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Section: Discussionmentioning

confidence: 47%

Case report: Effectiveness of sirolimus in treating partial DiGeorge Syndrome with Autoimmune Lymphoproliferative Syndrome (ALPS)-like features

Mou

Chen

et al. 2023

Front. Pediatr.

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“…Bortezomib use in ITP treatment is limited in case reports. Therapy was successful in three out of four cases reported in the literature ( 95 – 98 ). However, use of additional immunosuppressive therapies could have a confounding effect on response to bortezomib.…”

Section: Treatment To Overcome Rituximab Resistancementioning

confidence: 88%

Rituximab resistance in ITP and beyond

Xiao

Murakhovskaya

2023

Front. Immunol.

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The pathophysiology of immune thrombocytopenia (ITP) is complex and encompasses innate and adaptive immune responses, as well as megakaryocyte dysfunction. Rituximab is administered in relapsed cases and has the added benefit of inducing treatment-free remission in over 50% of patients. Nevertheless, the responses to this therapy are not long-lasting, and resistance development is frequent. B cells, T cells, and plasma cells play a role in developing resistance. To overcome this resistance, targeting these pathways through splenectomy and novel therapies that target FcγR pathway, FcRn, complement, B cells, plasma cells, and T cells can be useful. This review will summarize the pathogenetic mechanisms implicated in rituximab resistance and examine the potential therapeutic interventions to overcome it. This review will explore the efficacy of established therapies, as well as novel therapeutic approaches and agents currently in development.

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“…Considering that HD-IVIG requires four to five times the dose employed in patients on IgRT, further studies to validate the standardized protocols, while reconsidering the benefits, risks, cost-effectiveness, and different administration routes of immunoglobulins, for children with immune-dysregulation disorders, are needed to guide clinicians towards a thoughtful and responsible employment of this important medical product and to improve the therapeutical decisional process. The field is waiting for the development and validation of alternative and/or complementary immunomodulatory therapies reducing the demand for HD immunoglobulins [3], such as FcRn inhibitors (nipocalimab, rozanolixizumab, batoclimab, and efgartigimod), which are presently in clinical trials for CIDP and MG treatment [292,293]; an anti-CD19 antibody provoking B-cell exhaustion (inebilizumab) and an anti-IL-6 receptor antibody affecting the B-and T-cell maturing process (satralizumab), which are, to date, under investigation for use in NMOSD [294,295]; the proteasome inhibitor bortezomib, anecdotally used for pediatric refractory ITP [296]; and novel complement inhibitors (zilucoplan and ravulizumab), at present in clinical trials for subjects with MG [297].…”

Section: Discussionmentioning

confidence: 99%

Anti-Inflammatory and Immunomodulatory Effect of High-Dose Immunoglobulins in Children: From Approved Indications to Off-Label Use

Conti,

Moratti,

Leonardi

et al. 2023

Cells

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Background: The large-scale utilization of immunoglobulins in patients with inborn errors of immunity (IEIs) since 1952 prompted the discovery of their key role at high doses as immunomodulatory and anti-inflammatory therapy, in the treatment of IEI-related immune dysregulation disorders, according to labelled and off-label indications. Recent years have been dominated by a progressive imbalance between the gradual but constant increase in the use of immunoglobulins and their availability, exacerbated by the SARS-CoV-2 pandemic. Objectives: To provide pragmatic indications for a need-based application of high-dose immunoglobulins in the pediatric context. Sources: A literature search was performed using PubMed, from inception until 1st August 2023, including the following keywords: anti-inflammatory; children; high dose gammaglobulin; high dose immunoglobulin; immune dysregulation; immunomodulation; immunomodulatory; inflammation; intravenous gammaglobulin; intravenous immunoglobulin; off-label; pediatric; subcutaneous gammaglobulin; subcutaneous immunoglobulin. All article types were considered. Implications: In the light of the current imbalance between gammaglobulins’ demand and availability, this review advocates the urgency of a more conscious utilization of this medical product, giving indications about benefits, risks, cost-effectiveness, and administration routes of high-dose immunoglobulins in children with hematologic, neurologic, and inflammatory immune dysregulation disorders, prompting further research towards a responsible employment of gammaglobulins and improving the therapeutical decisional process.

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Refractory immune thrombocytopenia successfully treated with bortezomib in a child with 22q11.2 deletion syndrome, complicated by Evans syndrome and hypogammaglobulinemia

Cited by 9 publications

References 15 publications

Case report: Effectiveness of sirolimus in treating partial DiGeorge Syndrome with Autoimmune Lymphoproliferative Syndrome (ALPS)-like features

Case report: Effectiveness of sirolimus in treating partial DiGeorge Syndrome with Autoimmune Lymphoproliferative Syndrome (ALPS)-like features

Rituximab resistance in ITP and beyond

Anti-Inflammatory and Immunomodulatory Effect of High-Dose Immunoglobulins in Children: From Approved Indications to Off-Label Use

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