Immune Hematology by Jenny M. Despotovic

Author:Jenny M. Despotovic
Language: eng
Format: epub
Publisher: Springer International Publishing, Cham

ALPS

Autoimmune lymphoproliferative syndrome (ALPS) is a genetic disorder of defective lymphocyte apoptosis that is characterized by chronic nonmalignant lymphoproliferation, autoimmune diseases, and increased risk of malignancy. Abnormal TCRαβ+CD4−CD8− (double-negative) T lymphocytes are the signature of the disease, and their detection in peripheral blood is essential to establish the diagnosis [53]. Chronic, recurrent, multilineage cytopenia is the most common autoimmune manifestation of ALPS and the most common indication for treatment. Treatment of autoimmune cytopenia is needed in 59% of patients, but the need for treatment appears to decline with age [54]. ALPS-associated immune cytopenia is chronic, and a steroid-sparing agent should be considered early.

High-dose steroid pulses (5–10 mg/kg of intravenous methylprednisolone for 7–10 days) followed by a slow taper, with or without IVIG, is the recommended starting therapy [55]. MMF and sirolimus are the most studied steroid-sparing agents for ALPS. The majority of ALPS patients (60/64) treated with MMF for chronic cytopenia achieved an initial response lasting for at least 1 year, although one third (20 patients) relapsed and required other therapies [55]. Based on these results, MMF is considered the next treatment option after the acute presentation [55]. Sirolimus also led to a complete and durable response in 12 ALPS patients with cytopenia, including 7 patients who failed MMF [34]. Sirolimus is considered a secondary maintenance treatment for ALPS, especially in patients who fail MMF or have severe disease. Both MMF and sirolimus are well-tolerated in ALPS . Sirolimus has the unique benefit of directly targeting the double-negative T cells and lymphoproliferation in ALPS patients [34].

Second-line therapies for AIHA, namely, rituximab and splenectomy , should be avoided in ALPS. Rituximab is less effective in ALPS-related AIHA compared to primary AIHA and more toxic. In 12 ALPS patients treated with rituximab, 6/9 with ITP and 0/3 with AIHA had a clinical response. Importantly, three patients experienced prolonged hypogammaglobulinemia due to irreversible B-cell depletion which lasted several years [56]. Therefore, rituximab is not recommended for ALPS patients unless other treatment options are exhausted. Finally, splenectomy is associated with increased risk of mortality in ALPS . In a large cohort of ALPS patients, 40% underwent splenectomy, mostly before effective therapies or the diagnosis of ALPS were available. The likelihood of cytopenia relapse postsplenectomy was 30% by 4 years and >70% by 20 years. Importantly, 41% of splenectomized patients experienced at least one episode of sepsis and 9% died of overwhelming sepsis [54]. These poor results of splenectomy in ALPS, likely related to defective B-cell function, [26] indicate that splenectomy should be avoided in ALPS. Targeting T-cell pathology with MMF and sirolimus in ALPS , a primary disorder of T-cell dysregulation, is an example of a mechanism-based treatment approach that has proved to be more successful than conventional B-cell therapies, despite the apparent similarities between ALPS-related cytopenia and primary immune-mediated cytopenia [57].

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