Response to mercaptopurine for refractory autoimmune cytopenias in children

Sobota, Amy; Neufeld, Ellis J.; Lapsia, Sameer; Bennett, Carolyn M.

doi:10.1002/pbc.21729

Cited by 23 publications

(22 citation statements)

References 18 publications

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“…Data is limited on the use of other immunosuppressants and chemotherapeutic agents in patients with ALPS. Anecdotal reports and small series have described responses to a number of medications, including cyclosporine, vincristine, mercaptopurine, and methotrexate (Drappa et al, 1996;Sneller et al, 1997;Heelan et al, 2002;Rao et al, 2005;Sobota et al, 2009). Based on these reports, these agents have been recommended as third line in ALPS treatment algorithms (Rao et al, 2009b).…”

Section: Type Mutation 1amentioning

confidence: 99%

Advances in the management and understanding of autoimmune lymphoproliferative syndrome (ALPS)

Teachey¹,

Seif²,

2009

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SummaryAutoimmune lymphoproliferative syndrome (ALPS) is a disorder of T cell dysregulation caused by defective Fasmediated apoptosis. Patients with ALPS can develop a myriad of clinical manifestations including lymphadenopathy, hepatosplenomegaly, autoimmunity and increased rates of malignancy. ALPS may be more common that originally thought, and testing for ALPS should be considered in patients with unexplained lymphadenopathy, hepatosplenomegaly, and/or autoimmunity. As the pathophysiology of ALPS is better characterized, a number of targeted therapies are in preclinical development and clinical trials with promising early results. This review describes the clinical and laboratory manifestations found in ALPS patients, as well as the molecular basis for the disease and new advances in treatment.

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Section: Type Mutation 1amentioning

confidence: 99%

Advances in the management and understanding of autoimmune lymphoproliferative syndrome (ALPS)

Teachey¹,

Seif²,

2009

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“…There have been reports of successful clinical use of other agents, including hydroxychloroquine, dapsone, azathioprine, and 6-mercaptopurine, for the relief of chronic cytopenias in children and adults, and they should also be considered as a viable option in some patients with ALPS. 74,75 Role of HSCT in ALPS Both short and long prognosis of most ALPS patients appears to be good. In our entire cohort consisting of 257 persons, only13 ALPS patients have died: 8 because of postsplenectomy sepsis, 1 because of overwhelming hemolytic anemia and toxicities of its treatment, and 4 because of progressive malignancy.…”

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confidence: 99%

How I treat autoimmune lymphoproliferative syndrome

Rao

Oliveira²

2011

Blood

165

153

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Autoimmune lymphoproliferative syndrome (ALPS) represents a failure of apoptotic mechanisms to maintain lymphocyte homeostasis, permitting accumulation of lymphoid mass and persistence of autoreactive cells that often manifest in childhood with chronic nonmalignant lymphadenopathy, hepatosplenomegaly, and recurring multilineage cytopenias. Cytopenias in these patients can be the result of splenic sequestration as well as autoimmune complications manifesting as autoimmune hemolytic anemia, immune-mediated thrombocytopenia, and autoimmune neutropenia. More than 300 families with hereditary ALPS have now been described; nearly 500 patients from these families have been studied and followed worldwide over the last 20 years by our colleagues and ourselves. Some of these patients with FAS mutations affecting the intracellular portion of the FAS protein also have an increased risk of B-cell lymphoma. The best approaches to diagnosis, followup, and management of ALPS, its associated cytopenias, and other complications resulting from infiltrative lymphoproliferation and autoimmunity are presented. This trial was registered at www.clinicaltrial.gov as #NCT00001350. (Blood. 2011;118(22): 5741-5751) IntroductionAutoimmunity results from failure of self-tolerance, which can be further divided into central and peripheral tolerance. Central tolerance is fostered by apoptosis through elimination of autoreactive lymphocytes in generative lymphoid organs (the bone marrow and thymus), whereas mechanisms of peripheral tolerance include anergy, deletion by apoptosis, and suppression by regulatory T cells to avoid autoimmunity and tissue damage. 1 Apoptosis, the intrinsic program of cell death, is triggered by receptor-ligand interactions at the cell surface (the extrinsic pathway) or by the activation of mitochondrial proteins (the intrinsic pathway), leading to processing and activation of caspases and their downstream targets. Lymphocyte apoptosis mediated by the cell surface receptor FAS plays a pivotal role in lymphocyte homeostasis. FAS (also termed CD95/APO1) is a member of the tumor necrosis factor receptor superfamily of proteins that directly trigger apoptosis to maintain lymphocyte homeostasis and peripheral immune tolerance and prevent autoimmunity. 2,3 It is a membrane-bound molecule that is highly expressed, not only on activated B and T lymphocytes but also present in other cells, such as hepatocytes. FAS is present on the cell surface as a preformed trimer. 4 Its binding with FAS ligand leads to conformational changes on the intracellular portion of FAS protein triggering rapid recruitment of the death domain of the adaptor protein FADD (Fas-associated death domain) to the homologous death domain in the cytoplasmic tail of FAS. This is followed by the recruitment of procaspases 8 or 10 through the interaction of their death-effecter domains with the amino termini of FADD. The resulting Fas/FADD/caspase complex is termed the death-inducing signaling complex that incites a further cascade of caspase activation culminati...

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“…In that series of 29 patients, there was an 83% response rate, yet only 4 children (2 with ITP) remained in remission without additional immunosuppressive therapy. 75 Major toxicities of azathioprine and 6-mercaptopurine include myelosuppression, hepatotoxicity, and pancreatitis.…”

Section: Tiermentioning

confidence: 99%

How I treat refractory immune thrombocytopenia

Cuker

Neunert

2016

Blood

129

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This article summarizes our approach to the management of children and adults with primary immune thrombocytopenia (ITP) who do not respond to, cannot tolerate, or are unwilling to undergo splenectomy. We begin with a critical reassessment of the diagnosis and a deliberate attempt to exclude nonautoimmune causes of thrombocytopenia and secondary ITP. For patients in whom the diagnosis is affirmed, we consider observation without treatment.Observation is appropriate for most asymptomatic patients with a platelet count of 20 to 30 3 10 9 /L or higher. We use a tiered approach to treat patients who require therapy to increase the platelet count. Tier 1 options (rituximab, thrombopoietin receptor agonists, low-dose corticosteroids) have a relatively favorable therapeutic index. We exhaust all Tier 1 options before proceeding to Tier 2, which comprises a host of immunosuppressive agents with relatively lower response rates and/or greater toxicity. We often prescribe Tier 2 drugs not alone but in combination with a Tier 1 or a second Tier 2 drug with a different mechanism of action. We reserve Tier 3 strategies, which are of uncertain benefit and/or high toxicity with little supporting evidence, for the rare patient with serious bleeding who does not respond to Tier 1 and Tier 2 therapies. (Blood. 2016;128(12): 1547-1554 Case 1A 10-year-old male was diagnosed with primary immune thrombocytopenia (ITP) 5 months ago when he presented with epistaxis, petechiae, bruising, and a platelet count of 5 3 10 9 /L. He responded transiently to intravenous immunoglobulin G (IgG), but epistaxis recurred 2 weeks later. He subsequently received a short course of oral corticosteroids to which he had a temporary response in platelet count and cessation of epistaxis. Since discontinuing corticosteroids, he has had only occasional bruising and petechiae. His platelet count is currently 13 3 10 9 /L. He states that ITP is not interfering with activities.

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Response to mercaptopurine for refractory autoimmune cytopenias in children

Cited by 23 publications

References 18 publications

Advances in the management and understanding of autoimmune lymphoproliferative syndrome (ALPS)

Advances in the management and understanding of autoimmune lymphoproliferative syndrome (ALPS)

How I treat autoimmune lymphoproliferative syndrome

How I treat refractory immune thrombocytopenia

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