Approach Considerations
The treatment key of ALPS depends upon the patient’s manifestations and the disease complications. Upon confirmation of a diagnosis of ALPS, patients should undergo counseling aimed at specifically addressing the natural history, the disease manifestations, and the risks and complications associated with ALPS and its treatment.
The patient and the family should be educated on the risks associated with significant cytopenias (anemia, thrombocytopenia, neutropenia) and other autoimmune diseases that can develop and require immediate medical attention, such as systemic constitutional symptoms, petechiae, or mucosal bleeding. The increased risk of lymphomas and other malignancies should be addressed, especially in ALPS with FAS mutations, and patients should be encouraged to seek further evaluation for any severe or sudden fluctuations in a lymph node or spleen size. The increased risk of severe infections, especially pneumococcal sepsis associated with splenectomy, which is compounded by lack of memory B cells and autoimmune neutropenia, should be discussed.
The massive lymphadenopathy seen in children with ALPS can evoke considerable anxiety in patients and families, and as a result, clinicians may feel inclined to treat these patients for cosmetic purposes alone. However, corticosteroids or immunosuppressive drugs (e.g., azathioprine, cyclosporine, or mycophenolate mofetil) do not consistently shrink the lymph nodes and spleens of ALPS patients, and their use to treat these patients for solely cosmetic purposes is not indicated. [45]
The surgical role in ALPS is limited to lymph node biopsies. Splenectomy for chronic refractory cytopenias should be avoided since it increases significant risk of sepsis and is often ineffective and rarely leads to permanent remission. Hematopoietic stem cell transplantation (HSCT), the only curative treatment, is considered only in severe clinical phenotypes with no response to immune suppressive medications. [6]
Patients with ALPS are admitted to the hospital on a limited basis—generally, only to treat a critical care emergency (e.g., fever, sepsis, mucocutaneous bleeding, profound anemia, or thrombocytopenia or systemic autoimmune diseases). Conditions associated with ALPS, such as Hodgkin lymphoma and non-Hodgkin lymphoma, may require more extensive hospitalization. Other treatments are usually provided in an outpatient or home setting.
Outpatient care must be individualized. A team approach with appropriate consultants (see Consultations) should emphasize activities of daily living (to include school attendance), proper nutrition, and a healthy and positive attitude. Treatment teams should monitor medications used, as well as medication compliance, and admit patients to the hospital only for definitive medical or surgical treatment. Patients who have undergone splenectomy should wear medical alert bracelets or necklaces or carry wallet cards outlining their risk for sepsis.
Pharmacologic Therapy
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.
All ALPS patients who are asplenic should be treated with long-term antibiotic (e.g., penicillin V) prophylaxis against pneumococcal sepsis. These patients are often unable to produce or maintain protective antibodies against polysaccharide antigens after vaccination because of deficient memory B-cell function. Nevertheless, they should be vaccinated against encapsulated organisms such as pneumococcus, meningococcus, and Haemophilus influenzae type B (HIB) and should wear an appropriate alert bracelet citing their increased risk of infection.
Hematopoietic Stem Cell Transplantation (HSCT)
For reasons that remain unclear, the cytopenias in most patients with ALPS improve with age. Nevertheless, hematopoietic stem cell transplantation (HSCT) has been successful in ALPS patients and can be considered a treatment option for those with severe, recalcitrant disease and a matched donor. Sibling donors should be screened for and should be free of a mutation in the apoptosis pathway.
The mortality of a matched unrelated donor-derived allogeneic bone marrow transplant is too high to warrant the procedure in most ALPS patients, many of whom have a near-normal life expectancy. Most patients with cytopenias secondary to ALPS can be managed with immunosuppressive agents. Few patients with recalcitrant autoimmune cytopenias are sick enough as a result of their cytopenias to justify the risks and mortality associated with allogeneic bone marrow transplantation. [45]
Consultations
As with many chronic illnesses in pediatric or adult medicine, a team approach is required to serve the patient best. A pediatric hematologist and immunologist experienced in diagnosing and treating patients with ALPS and associated cytopenias should act as the treatment team leader. The team should also include a geneticist, a rheumatologist, an occupational therapist, a general pediatrician or internist, and a social worker.
School attendance, compliance with prescribed medications, and plans of action for febrile episodes in asplenic individuals should be discussed and reinforced. Telemedicine may play a role in long-distance consultation and treatment of patients with ALPS who reside at greater distances from full-service institutions.
Diet and Activity
No specific diets, dietary supplements, or dietary avoidances have been shown to have a significant effect on the course of ALPS.
Physical activity is encouraged in patients with ALPS. Patients with associated splenomegaly should avoid contact sports (eg, football, ice hockey) because of the increased risk of splenic rupture.
To help reduce the risk of traumatic splenic rupture, spleen guards made of fiberglass by an occupational therapist familiar with making such devices for children should be considered in ALPS patients who have massive splenomegaly. This is particularly important for those who are physically active (ie, nearly every toddler) and for children involved in competitive sports.
Prevention
Although specific mutations that cause ALPS have been identified, no environmental exposures or risk factors have yet been associated with an increased prevalence of the disease. Certainly, any patient with a personal or family history of ALPS should be encouraged to undergo genetic counseling and testing by a geneticist. No other preventive recommendations are currently available for patients with ALPS, except for diligent adherence to care plans in patients who have undergone splenectomy.
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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.
Tables
| Disease | Mutation | Clinical Features |
|---|---|---|
| Caspase-8 deficiency state (CEDS) | Autosomal recessive/ LOF mutation in CASP8 gene (2q33.1) | Recurrent sinopulmonary infections, severe mucocutaneous herpes simplex viral infection with defects in activation of T, B and NK cells, hypogammaglobulinemia, low pneumococcal antibodies, low T cell function (lymphocyte mitogen stimulation), low NK function [18] |
| FADD deficiency | Autosomal recessive/ LOF mutation in FADD gene (11q13.3) | Susceptibility to bacterial and viral infections related to functional hyposplenism and impaired interferon immunity, congenital heart disease, recurrent fever, liver dysfunction, seizures [19] |
| Ras-associated autoimmune leukoproliferative disorder | Germline or somatic mutations/ GOF mutation in NRAS gene (1p13.2) and KRAS gene (12p12.1) | Lymphadenopathy, massive splenomegaly, increased circulating B cells, hypergammaglobulinemia, autoimmunity [20, 21, 22] |
| Dianzani autoimmune lymphoproliferative disease | N252S and A91B perforin gene variations, osteopontin polymorphism | No increased DNT, defective Fas, lymphadenopathy, splenomegaly, autoimmunity [23, 24] |
| Activated phosphoinositide 3-kinase δ syndrome (APDS) | Autosomal dominant/ gain of function mutations in PIK3CD (1p36.22), PIK3R1(5q13.1) | Combined immunodeficiency with recurrent sinopulmonary infections, lymphadenopathy, herpesvirus infection, autoinflammatory disease, lymphoma and neurodevelopmental delay [25] |
| Protein kinase C delta (PRKCD) deficiency | Autosomal recessive/ loss of function mutation in PRKCD gene (3p21.1) | Hypogammaglobinemia, recurrent infections, lymphadenopathy, hepatosplenomegaly, autoimmunity and NK cell dysfunction [26, 27] |
| Lipopolysaccharide responsive and beige like anchor protein (LABA) deficiency with autoantibodies, regulatory T cell defects, autoimmune infiltration and enteropathy (LATAIE) | Autosomal recessive/ loss of function mutation in LPS-responsive and beige-like anchor protein (LABA) gene (4q31.3) | Autoimmunity, chronic diarrhea, enteropathy or IBD–like disease, splenomegaly, pneumonia, reduction in number of regulatory T cell, CD4 T cells, class-switched memory B cell and hypogammaglobinemia [28] |
| CTLA4 haloinsufficiency with autoimmune infiltration (CHAI) | Autosomal dominant/ LOF in CTLA4 gene (2q33.2) | Hypogammaglobulinemia, lymphoproliferation, autoimmune cytopenia, and respiratory, gastrointestinal, or neurological symptoms [29] |
| GOF mutations in STAT1 | Autosomal dominant/ GOF mutation in STAT1 gene (2q32.2) | Recurrent infections including chronic mucocutaneous candidiasis (CMC), recurrent Staphylococcus aureus, recurrent herpes, Mycobacterium, autoimmunity, cytopenia and aneurysm [30] |
| GOF mutations in STAT3 | Autosomal dominant/ GOF mutation in STAT3 gene (17q21.2) |
Hypogammaglobulinemia, autoimmunity, cytopenia, lymphadenopathy, splenomegaly, enteropathy, interstitial lung disease, endocrinopathy, postnatal growth failure [31, 32] |
Deficiency of adenosine deaminase 2 (DADA2) |
Autosomal recessive adenosine deaminase-2 (ADA2) gene (22q11.1) | Recurrent fever, vasculitis, aneurysms, hypertension, ischemic or hemorrhagic stroke, livedo reticularis, lymphadenopathy, hepatosplenomegaly,hypogammaglobulinemia, cytopenia, lymphopenia [33, 34] |
| B cell expansion with NF-B and T cell anergy disease (BENTA) | Autosomal dominant, GOF mutation in CARD11 gene (7p22.2) | Lymphadenopathy, splenomegaly, autoimmunity, cytopenia, low antibodies, recurrent bacterial infections, chronic viral (EBV, molluscum) infections, B cell lymphoma [35, 36] |
Deregulation of Fas ligand expression caused by IL-12RB1 mutation |
Autosomal recess, LOF mutation in IL12RB1 gene (19p13.11) | Lymphadenopathy, splenomegaly, hepatomegaly, elevated numbers of double-negative T cells, autoimmune cytopenias, and increased levels of vitamin B12 and interleukin-10 [37] |
| X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia” (XMEN) | LOF mutation in MAGT1 gene (Xq21.1) | Persistent Epstein–Barr virus (EBV) viremia, history of EBV+ lymphoma, a CD4:CD8 T-cell ratio of 1 or less with a normal lymphocyte count or mild to moderate lymphopenia, recurrent sinopulmonary and viral infections, hypogammaglobulinemia, variable antibody response to vaccinations, neutropenia, autoimmunity [38, 39] |
