An important aspect of caring for ALPS patients is the medical treatment of the chronic and refractory autoimmune cytopenias that frequently cause morbidity and even mortality in these patients.
Initial management of ALPS-related autoimmune cytopenias is corticosteroid therapy with or without high dose IVIG. Many patients often respond well to oral corticosteroids (1–2 mg/kg), and some require high-dose methylprednisolone (5–30 mg/kg/day for 1-3 days) followed by lower-dose prednisone (1–2 mg/kg/day) tapered slowly over months. High-dose (1–2 g/kg) intravenous immunoglobulin (IVIG) may be considered for concomitant use with pulse-dose steroids in those with severe AIHA. The IVIG treatment alone is less effective except ALPS with single-lineage autoimmune thrombocytopenia. However, the effect of IVIG is short-lived and requiries repeated infusion. A low-dose granulocyte colony-stimulating factor (G-CSF) 1–2 µg/kg subcutaneously 2–3 times weekly may be indicated in some patients with autoimmune neutropenia who experience significant infections.
MMF, an inosine-5’-monophosphate dehydrogenase reducing guanosine nucleotides in T and B cells, has been proven to be an effective steroid-sparing agent in 80% of ALPS. It does not require therapeutic drug monitoring, and it is a well-tolerated agent without significant drug-drug interaction. However, MMF does not affect lymphoproliferation or DNT cell depletion since it does not change the differentiation or mitotic activity of DNT cells. Some patients have partial responses and require prolonged corticosteroid therapy. [46]
Sirolimus or rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, has recently been successfully studied in ALPS. The evidence of hyperactive mTOR signaling of DNT cells and the abolished survival and proliferation of DNT cells in ALPS by sirolimus have supported the therapeutic role of sirolimus. [47] Sirolimus monotherapy has shown to be a safe and effective steroid-sparing agent with rapid improvement of autoimmune cytopenias, lymphadenopathy, splenomegaly, and undetectable DNT cells within 1 to 3 months [48] as well as normalization of Vit B12, IL-10, and soluble FASLG. [49] Since it is an extremely effective agent, sirolimus has been proposed to be the first-line therapy. [6] The primary drawback of sirolimus is the need for therapeutic drug monitoring (trough level of 5–15ng/ml). The well-known side effects are oral mucositis, hyperlipidemia, decreased renal function, myelosuppression, and drug-drug interaction.
Early use of MMF and sirolimus to minimize corticosteroid exposure is encouraged. A proposed treatment algorithm of ALPS with mild to moderate and moderate to severe autoimmune disease with or without clinically significant lymphoproliferation has been published. [6]
A small retrospective study that looked at the use of rituximab for the treatment of autoimmune cytopenias in ALPS found that whereas some ALPS patients with ITP showed improvement, ALPS patients with AIHA failed to show a significant improvement. [50] Furthermore, the use of rituximab in patients with ALPS-associated cytopenias led to significant toxicities, including hypogammaglobulinemia and neutropenia. Given the preexisting increased risk of infection in these patients, particularly those who are asplenic, rituximab should be avoided in this setting until all other immunosuppressive medication options have been exhausted. [45]
Other reported medications with limited use for refractory cytopenia in ALPS and ALPS-like disorders are pentostatin, bortezomib, the combination of methotrexate and sirolimus, and the combination of vincristine, methotrexate, and mercaptopurine.
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Examples of an autoimmune lymphoproliferative syndrome (ALPS) in a patient with grade IV (visible) lymphadenopathy.
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Autoimmune lymphoproliferative syndrome (ALPS) and ALPS-related disorders classification:
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Primary and accessory diagnostic criteria for autoimmune lymphoproliferative syndrome (ALPS).
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A patient with autoimmune lymphoproliferative syndrome (ALPS) who developed pneumococcal sepsis, a serious complication secondary to neutropenia and asplenia. Note the patient's cochlear implant; he has neurosensory hearing loss from prior episode of pneumococcal meningitis.
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Positron emission tomography (PET) superimposed over a CT scan from a patient with autoimmune lymphoproliferative syndrome (ALPS). Note the massive cervical adenopathy. PET scans may be used as a screening tool in patients with autoimmune lymphoproliferative syndrome to decrease the number of lymph node biopsies used in screening for malignancy.
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The extrinsic pathway of apoptosis. Mutations have been identified in each of the genes coding for Fas, Fas-ligand (FasL), caspase-8, and caspase-10. This figure was previously published in Rao VK, Straus SE. Autoimmune Lymphoproliferative Syndrome. Clinical Hematology. 58;759. 2006: Elsevier.
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Suggested treatment algorithm for patients with autoimmune lymphoproliferative syndrome (ALPS). This schematic diagram is included only as a suggested guideline for managing children with autoimmune lymphoproliferative syndrome–associated autoimmune multilineage cytopenias. Use of granulocyte-colony stimulating factor (G-CSF) may be warranted for severe neutropenia associated with systemic infections. Similarly, use of other chemotherapeutic and immunosuppressive agents (eg, vincristine, methotrexate, mercaptopurine, azathioprine, cyclosporine, hydroxychloroquine, tacrolimus, sirolimus) besides mycophenolate mofetil (MMF) should be considered as a steroid-sparing measure or while avoiding or postponing surgical splenectomy at the discretion of the treating clinicians based on the circumstances of a specific patient.
