Hematopoietic stem cell transplant in patients with activated PI3K delta syndrome

Nademi, Zohreh; Slatter, Mary; Dvorak, Christopher C.; Neven, Bénédicte; Fischer, Alain; Suarez, Félipe; Booth, Claire; Rao, Kanchan; Laberko, Alexandra; Rodina, J.; Bertrand, Yves; Kołtan, Sylwia; Dębski, Robert; Flood, Terence; Abinun, Mario; Gennery, Andrew R.; Hambleton, Sophie; Ehl, Stephan; Cant, Andrew J.

doi:10.1016/j.jaci.2016.09.040

Cited by 91 publications

(69 citation statements)

References 10 publications

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“…Gain‐of‐function mutation in PI3K ‐δ leads to increased activity in the p110δ catalytic protein (a product of PIK3CD gene), the subunit of PI3K ‐δ . Germline, autosomal dominant mutations lead to the clinical entity called APDS (also called PASLI [P110δ activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency]), wherein patients may suffer from recurrent respiratory infections and progressive airway damage, autoimmune cytopenias, lymphopenia, increased numbers of circulating transitional B cells, increased serum IgM levels, lymphoid hyperplasia, increased risk for malignancy, and impaired vaccine responses . Splice site mutations in PIK3R1 also appear to cause a phenotype similar to APDS …”

Section: Common Variable Immunodeficiencymentioning

confidence: 99%

“…77,78 Germline, autosomal dominant mutations lead to the clinical entity called APDS (also called PASLI [P110 activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency]), wherein patients may suffer from recurrent respiratory infections and progressive airway damage, autoimmune cytopenias, lymphopenia, increased numbers of circulating transitional B cells, increased serum IgM levels, lymphoid hyperplasia, increased risk for malignancy, and impaired vaccine responses. [77][78][79][80][81][82][83] Splice site mutations in PIK3R1 also appear to cause a phenotype similar to APDS. 82,84 Given that PI3K-serves in B-cell proliferation and survival sig- has demonstrated inhibitition of PI3K-signaling and decreased cell viability in B-cell leukemia lines.…”

Section: Activated Phosphoinositide 3-kinase-(pi3k-) Syndromementioning

confidence: 99%

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Diagnosis and management of chronic and refractory immune cytopenias in children, adolescents, and young adults

Rotz

Ware

Kumar

2018

Pediatric Blood & Cancer

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Children, adolescents, and young adults with chronic refractory autoimmune cytopenias represent a rare but challenging group of patients, who are managed frequently by pediatric hematologists. Novel diagnostic tests and genomic discoveries are refining historical diagnoses of Evans syndrome and common variable immunodeficiency, while also elucidating the cellular and molecular basis for these disorders. Genetic characterization of chronic and refractory autoimmune cytopenias has led to targeted therapies with improved clinical outcomes and fewer off-target toxicities. In this review, we focus on the appropriate diagnostic workup, expanded genetic testing, and novel treatment opportunities that are available for these challenging patients.

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Section: Common Variable Immunodeficiencymentioning

confidence: 99%

Section: Activated Phosphoinositide 3-kinase-(pi3k-) Syndromementioning

confidence: 99%

Diagnosis and management of chronic and refractory immune cytopenias in children, adolescents, and young adults

Rotz

Ware

Kumar

2018

Pediatric Blood & Cancer

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“…The results suggest that a large proportion of these rare diseases have required HCT and provide preliminary overview of HCT outcomes. While previous reports of HCT survival in selected PIRD genotypes have ranged from 40 to 80%, this is the first attempt to gain a broader overview of HCT outcomes for clinical features of "immune dysregulation" (2,3,(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). For this reason, the study was intentionally broad in scope and captured only a limited data set of key clinical features and outcomes from these patients.…”

Section: Discussionmentioning

confidence: 99%

Hematopoietic Cell Transplantation in Patients With Primary Immune Regulatory Disorders (PIRD): A Primary Immune Deficiency Treatment Consortium (PIDTC) Survey

et al. 2020

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Primary Immune Regulatory Disorders (PIRD) are an expanding group of diseases caused by gene defects in several different immune pathways, such as regulatory T cell function. Patients with PIRD develop clinical manifestations associated with diminished and exaggerated immune responses. Management of these patients is complicated; oftentimes immunosuppressive therapies are insufficient, and patients may require hematopoietic cell transplant (HCT) for treatment. Analysis of HCT data in PIRD patients have previously focused on a single gene defect. This study surveyed transplanted patients with a phenotypic clinical picture consistent with PIRD treated in 33 Primary Immune Deficiency Treatment Consortium centers and European centers. Our data showed that PIRD patients often had immunodeficient and autoimmune features affecting multiple organ systems. Transplantation resulted in resolution of disease manifestations in more than half of the patients with an overall 5-years survival of 67%. This study, the first to encompass disorders across the PIRD spectrum, highlights the need for further research in PIRD management.

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“…Although long-term treatment with rapamycin may be highly beneficial in patients with APDS 2, it is also associated with the risk of adverse events outside the immune system [8]. In patients with severe APDS, especially those with enhanced lymphoproliferation and profound lymphocyte dysfunction, allo-HSCT seems to be a therapeutic option, considering the potential risk of neoplastic transformation [6,8,12,13]. We have implemented immunoglobulin replacement therapy in both our patients.…”

Section: Discussionmentioning

confidence: 99%

Activated phosphoinositide 3-kinase delta syndrome 1 and 2 (APDS 1 and APDS 2): similarities and differences based on clinical presentation in two boys

Ewertowska

Grześk

Urbańczyk

et al. 2020

Allergy Asthma Clin Immunol

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Background: Activated PI3K delta syndrome (APDS) belongs to the heterogeneous group of primary immunodeficiency disorders (PIDs). Progress in next-generation sequencing (NGS) enabled identification of gain-offunction mutations in phosphoinositide 3-kinase (PI3K) genes. Depending on the type of causative mutation, APDS is classified into two types: APDS 1 and APDS 2. To date, less than 100 cases of APDS have been reported. Clinical symptoms of APDS result from impaired immune regulation and are clinically manifested by recurrent infections, allergies, lymphoproliferation and autoimmunity. They show similarity to other PIDs. Therefore, many patients were diagnosed incorrectly. The availability of genetic testing has allowed establishing the correct diagnosis in increasing number of patients suffering from APDS. Case presentations:The first male patient presented in infancy with recurrent infections. Subsequently he was found to suffer from hepatosplenomegaly, early portal hypertension, massive lymphoproliferation and hypogammaglobulinemia. The common E1021K mutation in the PI3KCD gene was identified. The patient underwent successful hematopoietic stem cell transplantation with resolution of most symptoms. The second patient suffered from persistent growth retardation since early life, facial dysmorphism and recurrent respiratory infections from early childhood. He was found to have systemic lympho-proliferation, panhypoglobulinemia and impaired antibody responses to vaccines. The introduction of NGS in Poland enabled rapid identification of a mutation in the PI3KR1 gene. Growth hormone administration seemed to have worsened the lymphoproliferation. Conclusions:Patients with suspected common variable immunodeficiency (CVID) and additional symptoms, such as allergy, facial dysmorphia, short stature, enhanced lymphoproliferation and lack of adequate response to human immunoglobulin replacement therapy, should be considered for NGS-based genetic testing. It may substantially shorten the time needed to establish the correct diagnosis, direct appropriate treatment and avoid potentially harmful therapies. To date, few cases of APDS have been described. It is important to report each of them to establish clinical indices and laboratory biomarkers of APDS 1 and APDS 2, to develop the standards of care in these conditions.

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Hematopoietic stem cell transplant in patients with activated PI3K delta syndrome

Cited by 91 publications

References 10 publications

Diagnosis and management of chronic and refractory immune cytopenias in children, adolescents, and young adults

Diagnosis and management of chronic and refractory immune cytopenias in children, adolescents, and young adults

Hematopoietic Cell Transplantation in Patients With Primary Immune Regulatory Disorders (PIRD): A Primary Immune Deficiency Treatment Consortium (PIDTC) Survey

Activated phosphoinositide 3-kinase delta syndrome 1 and 2 (APDS 1 and APDS 2): similarities and differences based on clinical presentation in two boys

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