Autoimmune Lymphoproliferative Syndrome

Clinical characteristics: Autoimmune lymphoproliferative syndrome (ALPS), caused by defective lymphocyte homeostasis, is characterized by the following:

1. Non-malignant lymphoproliferation (lymphadenopathy, hepatosplenomegaly with or without hypersplenism) that often improves with age

2. Autoimmune disease, mostly directed toward blood cells

3. Lifelong increased risk for both Hodgkin and non-Hodgkin lymphoma

In ALPS-FAS (the most common and best-characterized type of ALPS, associated with heterozygous germline pathogenic variants in FAS), non-malignant lymphoproliferation typically manifests in the first years of life, inexplicably waxes and wanes, and then often decreases without treatment in the second decade of life; in many affected individuals, however, neither splenomegaly nor the overall expansion of lymphocyte subsets in peripheral blood decreases. Although autoimmunity is often not present at the time of diagnosis or at the time of the most extensive lymphoproliferation, autoantibodies can be detected before autoimmune disease manifests clinically.

In ALPS-FAS caused by homozygous or compound heterozygous (biallelic) pathogenic variants in FAS, severe lymphoproliferation occurs before, at, or shortly after birth, and usually results in death at an early age.

ALPS-sFAS, resulting from somatic FAS pathogenic variants in selected cell populations, notably the alpha/beta double-negative T cells (α/β-DNT cells), appears to be similar to ALPS-FAS resulting from heterozygous germline pathogenic variants in FAS, although lower incidence of splenectomy and lower lymphocyte counts have been reported in ALPS-sFAS and no cases of lymphoma have yet been published.

Diagnosis/testing: The diagnosis of ALPS is based on the following:

1. Clinical findings

2. Laboratory abnormalities:

   1. Abnormal biomarker testing (soluble interleukin-10 [IL-10], Fas ligand [FasL], IL-18, and vitamin B₁₂)

   2. Defective in vitro tumor necrosis factor receptor superfamily member 6 (Fas)-mediated apoptosis

   3. T cells that express the alpha/beta T-cell receptor but lack both CD4 and CD8 (so-called "α/β-DNT cells")

3. Identification of pathogenic variants in genes relevant for the Fas pathway of apoptosis. These genes include FAS (either germline or somatic pathogenic variants), CASP10, and FASGL.

   Up to 20% of those with clinical ALPS have not had a genetic etiology identified.

Management: Treatment of manifestations: Current management is focused on monitoring for and treatment of lymphoproliferation, hypersplensim, and lymphomas and management of cytopenias and other autoimmune diseases. Corticosteroids and immunosuppressive therapy do not decrease lymphadenopathy long term and are generally reserved for severe complications of lymphoproliferation (e.g., airway obstruction, significant hypersplenism associated with splenomegaly) and/or autoimmune manifestations. Experience with sirolimus suggests that it is the preferred agent in treating lymphoproliferation in a more sustained manner, including maintenance of remission following a period of discontinued use of sirolimus; however, sirolimus is not without side effects. Lymphoma is treated with conventional protocols. Autoimmune cytopenias and other autoimmune diseases are typically treated by immune suppression with corticosteroids as well as corticosteroid-sparing agents if prolonged treatment of autoimmune cytopenias is required and/or in cases of refractory cytopenias.

Splenectomy is reserved as an option of last resort in the treatment of life-threatening refractory cytopenias and/or severe hypersplenia because of the high risk of recurrence of cytopenias and sepsis post-splenectomy in persons with ALPS.

Prevention of primary manifestations: Bone marrow (hematopoietic stem cell) transplantation (BMT/HSCT), the only curative treatment for ALPS, has to date mostly been performed on those with severe clinical phenotypes such as ALPS-FAS caused by biallelic pathogenic variants, those with severe and/or refractory autoimmune cytopenias, those with lymphoma, and those who have developed complications from (often long-term) immunosuppressive therapy.

Prevention of secondary complications: Vaccinations pre-splenectomy (with consideration of post-splenectomy boost vaccinations) and penicillin prophylaxis are strongly recommended for individuals who undergo splenectomy.

Surveillance: Clinical assessment and imaging and laboratory studies for manifestations of lymphoproliferation and autoimmunity; specialized imaging studies to detect malignant transformation.

Agents/circumstances to avoid: Splenectomy is discouraged as it typically does not lead to permanent remission of autoimmunity and is associated with increased risk of infection. Aspirin and other nonsteroidal anti-inflammatory drugs should be used with caution in individuals with immune thrombocytopenia as they can interfere with platelet function.

Evaluation of relatives at risk: If the pathogenic variant(s) have been identified in a family member with ALPS, it is appropriate to perform molecular genetic testing on at-risk relatives to allow for early diagnosis and treatment.

Pregnancy management: Assessment of the risks and benefits of treating a woman who has ALPS with corticosteroids, mycophenylate mofitil, or sirolimus during pregnancy must take into consideration the potential teratogenic risks to the fetus.

Genetic counseling: Inheritance of ALPS-CASP10, most cases of ALPS-FAS, and some cases of ALPS-FASLG is autosomal dominant. Each child of an individual with autosomal dominant ALPS has a 50% chance of inheriting the pathogenic variant. Inheritance of most cases of ALPS-FASLG and severe ALPS associated with biallelic FAS pathogenic variants is autosomal recessive. The parents of an individual with autosomal recessive ALPS are likely to be heterozygotes, in which case each has one FAS pathogenic variant; these parents may have ALPS-related findings or may be clinically asymptomatic.

Prenatal testing for a pregnancy at increased risk is possible if the pathogenic variant(s) have been identified in an affected family member.

ALPS-FAS can also be the result of somatic mosaicism. Somatic pathogenic variants have not been reported in ALPS-FASLG or ALPS-CASP10 to date.