Version May 2024
INTRODUCTION — Autoimmune lymphoproliferative syndrome (ALPS) is a rare inborn error of immunity characterized by dysregulation of the immune system due to an inability to regulate lymphocyte homeostasis through the process of lymphocyte apoptosis (a form of programmed cell death). The consequences include lymphoproliferative disease, manifested by lymphadenopathy, hepatomegaly, splenomegaly, and an increased risk of lymphoma, as well as autoimmune disease, typically involving blood cells.
This topic reviews management of ALPS. The epidemiology, genetics, pathogenesis, clinical manifestations, laboratory findings, diagnosis, and differential diagnosis of ALPS are discussed separately. (See "Autoimmune lymphoproliferative syndrome (ALPS): Epidemiology and pathogenesis" and "Autoimmune lymphoproliferative syndrome (ALPS): Clinical features and diagnosis".)
GOALS OF THERAPY — Management of ALPS focuses upon three aspects [1,2]:
●Treatment of disease manifestations
●Treatment/prevention of complications arising from the disease and its treatment
●Curative therapy
REFERRAL — Patients with evidence of lymphoproliferation, as manifested by enlarged lymph nodes, splenomegaly, and/or hepatomegaly, should be referred to an expert in oncology with experience in evaluating benign and malignant lymphoproliferative disease. In addition, patients with autoimmune cytopenias should be seen by an expert in hematology. Referral to a center of excellence for ALPS is an option either initially or after evaluation by an expert in hematology/oncology has taken place and a diagnosis of ALPS is suspected, likely, or confirmed.
EVALUATION FOLLOWING INITIAL DIAGNOSIS
Determination of disease extent and burden — The presence and extent (disease manifestations and disease burden) of lymphoproliferation and/or autoimmunity should be determined before initiating therapy in a person newly diagnosed with ALPS or suspected to have ALPS. Whether the patient needs to be treated and, if so, with which agent or agents are determined following this evaluation.
This evaluation can be achieved with a combination of:
●Physical examination that includes an inventory of lymph nodes and assessment for splenomegaly, as well as evaluation for presence of comorbidities such as atopic disease (see "Autoimmune lymphoproliferative syndrome (ALPS): Clinical features and diagnosis", section on 'Clinical manifestations of ALPS-FAS' and "Autoimmune lymphoproliferative syndrome (ALPS): Clinical features and diagnosis", section on 'Clinical features of other ALPS genotypes')
●Imaging studies that include computed tomography (CT) scan (often already performed before or during the initial diagnostic work-up) and/or positron emission tomography (PET) scan (typically only performed if there is a suspicion of lymphoma) of body areas thought to be involved (typically neck, chest, abdomen, and pelvis) to assess the degree of lymphoproliferation (see 'Lymphoma' below)
●Laboratory evaluation that includes measuring the size of the circulating alpha beta double-negative T (DNT) cell compartment, the levels of serum biomarkers (eg, vitamin B12, interleukin [IL] 10, IL-18, Fas ligand [FasL]), a complete blood count with differential, and the presence and nature of autoantibodies (eg, directed against blood cells) if not already performed as part of the initial diagnostic process (see "Autoimmune lymphoproliferative syndrome (ALPS): Clinical features and diagnosis", section on 'Laboratory findings')
Assessment of immune function — A basic investigation of the integrity of the immune system should be performed in patients deemed to need immunosuppressive therapy, particularly in young patients. In addition to the complete blood count with differential, these studies include quantitative immunoglobulin levels, antibody titers to protein (and, if over two years old, polysaccharide) vaccines, and CH50, as well as lymphocyte subsets and T cell function studies if contemplating long-term immunosuppressive therapy with sirolimus. In addition, prior to initiating some immunosuppressive therapies, it is important to rule out certain infections, including tuberculosis and human immunodeficiency virus (HIV). (See "Laboratory evaluation of the immune system" and 'Lymphoproliferation' below.)
Evaluation for lymphoma — The initial evaluation should also include an assessment for lymphoma in patients with extensive lymphadenopathy, especially in those with constitutional symptoms (eg, fever, weight loss, night sweats). Use of positron emission tomography (PET) based imaging to help distinguishing "good" from "bad" nodes on the basis of presumed higher metabolic activity of malignant lymphoid tissue has been investigated, but this approach is not validated [3]. PET scans fluctuate with respect to the localization of "hot" (chemically active) versus "cold" nodes in individual patients, contrasting with nodes that are more likely to be persistently hot. However, nonmalignant lymphadenopathy similarly varies over time. Other considerations are exposure to radiation and cost. Thus, PET imaging is not used as a routine surveillance tool. Education of patients/caregivers as to signs and symptoms of lymphoma (ie, different than "typical" ALPS) and routine follow-up may be as effective as imaging for lymphoma surveillance. However, all questionable nodes require biopsy and histologic evaluation, and PET scans can be useful in directing the surgeon to the node or nodes with high metabolic activity that are most likely to be of value for diagnostic excisional biopsy if there is suspicion of a lymphoma. Investigation for lymphoma is particularly important if immunosuppressive and/or immunomodulating agents are contemplated since lymphoma development may be altered and/or masked by use of these agents.
TREATMENT OF DISEASE MANIFESTATIONS
Overview — The management of disease manifestations is focused on the control/treatment of lymphoproliferation and/or autoimmunity and the treatment of lymphoma [2,4-9]. Most experience is confined to patients with ALPS-FAS, for whom lymphoproliferative disease begins early in life and tends to become less frequent in adolescence and adulthood. Patients can have mild cytopenias due to hypersplenism, which is different from the autoimmune cytopenias. Development of autoimmune manifestations, which invariably involve combinations of the autoimmune cytopenias (autoimmune hemolytic anemia and thrombocytopenia with or without neutropenia), signals a transition in the natural history of ALPS in many patients that is often characterized by the need to initiate or escalate therapy. Treatment of lymphoproliferation and autoimmune disease in ALPS is based upon observational data and clinical experience since there are no randomized trials. Therapy is individualized, and the choice of agent depends upon many patient-specific factors and practitioner preference and experience.
Autoimmune manifestations
Our approach — For patients with known ALPS disease who demonstrate a change in clinical phenotype, from "lymphoproliferation only" to "lymphoproliferation and autoimmunity," we suggest starting sirolimus treatment. For patients who develop severe autoimmune manifestations (primarily cytopenias), which may have sudden onset and be difficult to control, we suggest using a combination of sirolimus and immunomodulating agents. This combination typically includes high-dose intravenous immune globulin (IVIG) plus a course of prednisone at the start of therapy to establish control of autoimmunity, along with initiation of sirolimus. For patients who are on mycophenolate mofetil when an exacerbation of autoimmune disease occurs, we suggest switching to sirolimus, starting with a dose to keep drug levels at the lower end of the therapeutic range (usually 2 to 3 mg/m2/day). These patients typically have milder autoimmune manifestations and do not require concomitant treatment with prednisone.
Persistent hemolysis or severe thrombocytopenia may be controlled with rituximab as the immunomodulating agent, keeping in mind that the patient will experience loss of B cells, at least transiently, and may require immune globulin replacement secondary to development of hypogammaglobulinemia. (See "Autoimmune hemolytic anemia (AIHA) in children: Treatment and outcome" and "Immune thrombocytopenia (ITP) in children: Initial management".)
Autoimmune manifestations typically respond to therapy, but patients with autoimmune manifestations usually have a more difficult time coming off immunosuppressive agents than patients with lymphoproliferation only. Cumulative data (including published reports) favors the use of sirolimus. However, there are no controlled trials comparing sirolimus head-to-head with mycophenolate mofetil. In addition, ALPS does not demonstrate "spontaneous" (permanent) remissions. Thus, treatment options and decisions must take into account the potentially lifelong need for immunosuppression. (See "Autoimmunity in patients with inborn errors of immunity/primary immunodeficiency".)
Specific therapies — Specific therapies include immunosuppressive (eg, sirolimus, mycophenolate mofetil, prednisone) and immunomodulating (eg, high-dose intravenous immune globulin [IVIG], rituximab) agents. Uncommonly used therapies include plasmapheresis and proteosome inhibitors.
●Glucocorticoids given orally or in intravenous boluses, as is done to treat other autoimmune cytopenias, can be effective in acute, severe bouts of anemia or thrombocytopenia in ALPS. However, glucocorticoids are typically needed for prolonged periods of time. In addition, approximately 50 to 60 percent of patients are not adequately managed by glucocorticoid monotherapy, due to an incomplete initial response and/or recurrence with tapering/weaning glucocorticoids, and require additional immunosuppressive drugs to control autoimmunity [10,11]. Thus, patients are also treated with a steroid-sparing agent (eg, mycophenolate mofetil) [2].
●Sirolimus appears to be the most effective agent against chronic, recalcitrant autoimmune cytopenias and may enable weaning or avoidance of glucocorticoids [1,9,12-14]. A small, multiinstitutional, prospective study demonstrated efficacy of sirolimus monotherapy in ALPS [15]. All 12 treated patients achieved a durable complete response, including rapid improvement in autoimmune disease, lymphadenopathy, and splenomegaly within one to three months of starting sirolimus. These results have been duplicated by other investigators. Cyclosporine and tacrolimus are rarely used since the introduction of sirolimus. While mycophenolate mofetil may be helpful in individual patients, for example, those who want to avoid sirolimus or who do not tolerate it, there are no consistent data supporting its use in patients with ALPS patients with autoimmunity.
●Rituximab has been used successfully in the treatment of refractory cytopenias in ALPS, although it is not yet known how long affected persons will remain in clinical remission [9,16]. Monitoring B cell reconstitution following rituximab may help with estimating duration of remission and also with managing hypogammaglobulinemia post-rituximab. In patients with ALPS who are asplenic, drug-related adverse effects, including hypogammaglobulinemia and rituximab-induced neutropenia, add to the risk of sepsis or other serious infection [17].
●High-dose IVIG (1 g/kg once daily for two days) is sufficient to control cytopenias in some patients [4].
●Severe (recalcitrant) cytopenias or other potentially life-threatening autoimmune manifestations may require plasmapheresis in combination with other modalities, including bortezomib, a proteosome inhibitor [18].
Lymphoproliferation
Our approach — Lymphoproliferative complications alone (eg, airway obstruction from enlarged tonsillar tissue, massive splenomegaly) are almost never severe enough to require treatment with immunosuppressive agents. In addition, lymphoproliferation typically returns after cessation of immunosuppressive therapy [4] or, in the case of enlarged tonsillar tissue, after tonsillectomy [19]. Furthermore, adenopathy generally recedes over time and organomegaly may as well. Thus, we suggest observation and expectant management rather than immunosuppressive therapy for most patients with lymphoproliferation without autoimmune manifestations. Typical protective measures (eg, avoidance of contact sports to avoid splenic rupture) are taken in patients with splenomegaly. We recommend against splenectomy, because of lack of sustained benefit and a clear increased risk of post-splenectomy sepsis, which may be rapidly fatal. (See 'Avoidance of splenectomy' below.)
Immunosuppressive therapy is an alternative to observation, particularly in patients with a degree of lymphoproliferation that causes chronic symptoms and/or significantly compromises quality of life. The benefits of immunosuppression must be weighed against the side effects, particularly since lymphadenopathy as well as splenomegaly and/or hepatomegaly return once immunosuppression is discontinued [4]. Manifestations of lymphoproliferation can be decreased by the use of immunosuppressive agents, such as glucocorticoids, mycophenolate mofetil, sirolimus, tacrolimus, or cyclosporine [4,12,13]. The least immunosuppressive agent to accomplish treatment goals is chosen.
For most patients treated with immunosuppressive therapy for isolated lymphoproliferative disease, we suggest a two- to three-week course of prednisone (1 to 2 mg/kg/day) followed by a taper as tolerated combined with mycophenolate mofetil (300 to 600 mg/m2/day). Mycophenolate mofetil is then slowly weaned as guided by clinical response and/or side effects, including tolerability of the agent, physical examination (eg, degree of splenomegaly), and biomarkers to determine response and guide changes in drug dose (duration in therapy). It can be difficult to distinguish between spontaneous improvement of lymphoproliferation and medication effect, particularly in patients <10 years of age. The author typically follows clinical response and biomarkers at three-month intervals and treats for a least one year before contemplating a taper but rarely treats beyond five years. One approach to tapering is to not adjust the dose over time as the child grows, which gradually decreases the mg/kg dose the child receives.
In patients with an insufficient response or intolerance to mycophenolate mofetil or who experience new autoimmunity while on treatment, the necessity of long-term immunosuppressive therapy should be reaffirmed before switching to a more potent immunosuppressive agent with greater possible side effects (eg, sirolimus). Management of autoimmune manifestations is reviewed above. (See 'Autoimmune manifestations' above.)
Specific agents — Mycophenolate mofetil is typically well tolerated and requires little monitoring, making it a reasonable choice for initial maintenance therapy. It often induces modest improvement in lymphadenopathy and reduces levels of laboratory markers, such as lymphocyte counts and interleukin (IL) 10 and vitamin B12 levels [19]. In addition, it may lead to some improvement in splenomegaly in a portion of patients. Dose and duration of therapy should be individualized to the patient, using a minimal dose that accomplishes the goals of therapy.
Early experience with sirolimus suggests that this agent may affect lymphoproliferation in a more sustained manner than other immunosuppressive agents, as demonstrated by more significant reduction in adenopathy, splenomegaly, and biomarkers (eg, soluble IL-2 receptor alpha [sIL-2Ralpha], soluble Fas ligand, IL-10, IL-18, and vitamin B12) [13]. Increased mammalian (mechanistic) target of rapamycin (mTOR) pathway activation in ALPS may provide an explanation for the favorable action of sirolimus [20]. This is balanced by the fact that sirolimus requires monitoring of levels, interacts with other medications, and has side effects and associated complications, including infections. On the other hand, it is less mutagenic than mycophenolate mofetil, tacrolimus, and cyclosporine [21]. In addition, long-term use of calcineurin inhibitors (eg, tacrolimus, cyclosporine) is associated with kidney toxicity [22].
Lymphoma — Lymphoma is treated according to conventional protocols (see specific treatment topics for each type of lymphoma). The presence of defective Fas-mediated apoptosis does not appear to hinder the response to chemotherapeutic agents or radiation.
SURVEILLANCE — If the decision is made not to initiate treatment, periodic follow-up is recommended, employing the same tools used in the initial assessment (see 'Evaluation following initial diagnosis' above). The frequency of follow-up depends upon multiple factors, including the age of the patient, access to appropriate specialists, and patient/caregiver preferences. Many laboratory findings, including the number of double-negative T (DNT) cells and level of circulating interleukin (IL) 10, Fas ligand (FasL), and other biomarkers, serve not only a diagnostic purpose but also can indicate disease activity and response to therapy.
Periodic surveillance using combined anatomic (ie, computed tomography [CT] scan) and functional/metabolic (ie, positron emission tomography [PET] scan) imaging is unlikely to be helpful in monitoring efficacy and possibly determining the duration of need for sirolimus (see 'Evaluation for lymphoma' above) [3]. Mycophenolate mofetil does not lead to enough resolution of anatomic findings (adenopathy, splenomegaly) to justify periodic imaging and radiation exposure.
PREVENTION OF COMPLICATIONS
Planning for long-term therapy — Once initiated, immunosuppressive and/or immunomodulating therapy may be difficult to stop. This should be taken into consideration before starting therapy because of the side effects, risks, and high cost of long-term immunosuppressive treatment. The development of symptomatic autoimmune cytopenias often indicates a new phase of ALPS in a particular patient. Therapies that affect the immune system should not be used for extended periods of time (years), particularly in children, because of their complications. For example, long-term use of glucocorticoids is associated with obesity, growth retardation, hypertension, cataracts, osteopenia/osteoporosis leading to pathologic bone fractures, and diabetes, among others. Long-term use of antiproliferative T cell agents (eg, cyclosporine, tacrolimus) may cause significant infections and kidney impairment. In addition, the immune system may not withstand suppression for prolonged periods of time, and secondary immunodeficiency may persist. Resolution of ALPS manifestations after years of therapy may be due to chronic immunosuppression rather than permanent remission of ALPS, indicating the need for periodic assessment of overall immune competence. This is particularly important in younger patients as they experience common viral infections, such as those due to cytomegalovirus (CMV) and Epstein-Barr virus (EBV). (See "Major adverse effects of systemic glucocorticoids" and "Secondary immunodeficiency induced by biologic therapies".)
Avoidance of splenectomy — Splenectomy is not recommended in patients with ALPS, due to the reported lack of sustained therapeutic benefit and increased incidence of post-splenectomy sepsis in both children and adults. In the original French ALPS cohort, 33 percent of 90 patients underwent splenectomy (40 percent for massive splenomegaly and 60 percent for refractory autoimmune cytopenias) [10]. In the National Institutes of Health (NIH) ALPS cohort, 44 percent of 150 patients had been treated with splenectomy prior to referral, three-quarters for refractory cytopenias that typically involved more than one hematopoietic cell lineage [11]. Of the patients who had splenectomy for severe cytopenias, 50 percent in the French cohort relapsed, and 30 and >70 percent relapsed in the NIH cohort by 4 and 20 years post-splenectomy, respectively. Thrombocytopenia was the most common cytopenia seen in patients who relapsed.
An increased rate of sepsis in patients who had undergone splenectomy was also seen in both cohorts [10,11]. In the French cohort, 9 of 30 patients suffered 17 cases of severe invasive bacterial infections with four deaths, while 27 of 66 in the NIH cohort suffered one or more episodes of sepsis with seven deaths. Young age was a risk factor for sepsis after splenectomy. Antimicrobial prophylaxis and appropriate vaccinations had been prescribed in the majority of the episodes of sepsis, although poor adherence was found to be a risk factor for sepsis in the French cohort.
Avoidance of infections — Most complications in ALPS are the result of immunosuppressive and immunomodulating therapy and relate to the increased risk of infections or systemic side effects of glucocorticoids. (See "Major adverse effects of systemic glucocorticoids", section on 'General treatment considerations and monitoring' and "Secondary immunodeficiency induced by biologic therapies".)
Patients with ALPS are usually diagnosed after they have received their first round of childhood vaccines. In addition, they show normal response to vaccines, including coronavirus disease 2019 (COVID-19) vaccine. Required vaccines should be administered prior to the institution of glucocorticoid therapy, if possible, but do not need to be withheld in patients on nonglucocorticoid immunosuppressive therapy.
Intravenous or subcutaneous immune globulin replacement therapy is warranted in some cases of ALPS, as well as antimicrobials to prevent opportunistic, fungal, and viral infections in those on higher-impact immunosuppressive medications. Infections secondary to immunosuppression should be thoroughly investigated with cultures and aggressively treated. Immunodeficiency in the absence of immunosuppressive therapy is not typical in ALPS and should be worked up further. (See "Immune globulin therapy in inborn errors of immunity".)
In patients who have had a splenectomy, lifelong prophylaxis with penicillin or amoxicillin is required, and post-splenectomy booster vaccinations are advised. (See "Prevention of infection in patients with impaired splenic function", section on 'Daily antibiotic prophylaxis'.)
CURATIVE THERAPY — Hematopoietic cell transplantation (HCT) is the only curative treatment for ALPS [23,24]. Reduced-intensity preparative regimens offer lower morbidity and mortality than myeloablative preparative regimens and have been used successfully in inborn errors of immunity. One published protocol includes alemtuzumab, fludarabine, and melphalan as a reduced-intensity regimen that was well tolerated [25]. The status of ALPS disease activity should be carefully evaluated, and the potential consequences of long-term treatments, including impact on organ function, should be compared with the risks of transplantation before HCT is performed. (See "Hematopoietic cell transplantation for non-SCID inborn errors of immunity".)
Examples of transplant indications include:
●Lymphoma in relapse, high-risk lymphoma, or second primary lymphoma after therapy.
●Severe and recalcitrant autoimmune cytopenias, with disease manifestations controlled only by aggressive and sustained immunosuppression.
●Development of a significant immunodeficiency disorder during or following prolonged immunosuppressive therapy.
●Severe disease at the time of diagnosis, including but not limited to patients with homozygous or compound heterozygous FAS defects. This may also pertain to patients with complex genotypes, in which an additional genetic defect complicates management [26,27].
●Recurrent severe invasive bacterial infection or sepsis post-splenectomy despite adequate antimicrobial prophylaxis and booster vaccinations [28].
GENETIC COUNSELING — Genetic counseling is recommended to provide patients and families with information on the nature of the disease, its inheritance, and implications for affected relatives and carriers. Patients with ALPS due to somatic Fas pathogenic variants (ALPS-sFAS) did not inherit the genetic defect in FAS from either of the parents and do not appear to carry the pathogenic variant in their germline deoxyribonucleic acid (DNA). Consequently, their offspring will not inherit the somatic variant. In contrast, those with a constitutional FAS variant are at 50 percent risk of passing the variant on to each of their offspring, who may be affected to a greater or lesser degree than their parents due to the variable penetrance and expressivity of ALPS manifestations. In addition, manifestations of ALPS at an early age are not predictive of later life course.
PROGNOSIS — Many patients with ALPS have a favorable prognosis, with lymphadenopathy decreasing over time (even without treatment in mild disease) and autoimmune features remaining absent or manageable with limited need for immunosuppressive therapy. Some patients with particular pathogenic variants affecting the intracellular death domain of the Fas molecule may have a poorer prognosis, while those with defects in the extracellular domain may have more mild disease. However, it is impossible to predict which path each individual patient will follow, regardless of the genotype, and severe disease may arise for the first time in adulthood. Thus, long-term follow-up is indicated for the majority of patients to carefully monitor the course of each person's disease. A significant component of follow-up care should focus on education and empowerment of patients and their parents/caregivers. In addition, patients may need to be monitored for subsequent pathogenic events affecting Fas-mediated apoptosis, lymphocyte homeostasis in general, or other (still unknown) events [29].
Patients with pathogenic variants in FAS that affect the extracellular domains, particularly if these variants cause defective apoptosis through haploinsufficiency (rather than dominant-negative interference), may have less severe disease and/or be less at risk for lymphoma. This optimism needs to be balanced with the recognition of second genetic hits affecting FAS [29].
Patients with homozygous or compound heterozygous FAS pathogenic variants have very early onset, severe manifestations, and a worse prognosis that typically requires allogeneic bone marrow transplantation early in life in order to survive.
Longer-term follow-up of patients with ALPS-sFAS is needed to better assess the natural history of their clinical disease and their prognosis.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of immunity (previously called primary immunodeficiencies)".)
SUMMARY AND RECOMMENDATIONS
●Treatment of disease manifestations – Management of autoimmune lymphoproliferative syndrome (ALPS) focuses on control/treatment of lymphoproliferation and autoimmunity and early diagnosis and treatment of lymphoma. Therapy is individualized, and the choice of treatment depends upon patient-specific factors and clinician preference and experience. Our general approach is as follows:
•Autoimmune manifestations – The development of symptomatic autoimmune cytopenias (eg, autoimmune hemolytic anemia and thrombocytopenia with or without neutropenia) often indicates a new phase of ALPS and signals a need to initiate or escalate therapy.
-For patients with known ALPS disease who demonstrate a change in clinical phenotype, from "lymphoproliferation only" to "lymphoproliferation and autoimmunity," we suggest starting sirolimus treatment rather than mycophenolate mofetil (Grade 2C).
-For patients who develop severe autoimmune manifestations (primarily cytopenias), which may have sudden onset and be difficult to control, we suggest using a combination of sirolimus and immunomodulating agents (Grade 2C). This combination typically includes high-dose intravenous immune globulin (IVIG) plus a course of prednisone at the start of therapy to establish control of autoimmunity, along with initiation of sirolimus.
-For patients who are on mycophenolate mofetil when an exacerbation of autoimmune disease occurs, we suggest switching to sirolimus (Grade 2C), starting with a dose to keep drug levels at the lower end of the therapeutic range (usually 2 to 3 mg/m2/day).
-For patients who do not achieve/maintain remission with high-dose IVIG as the immunomodulatory agent, we suggest switching to rituximab (Grade 2C). (See 'Autoimmune manifestations' above and 'Avoidance of splenectomy' above.)
•Lymphoproliferation – We suggest observation and expectant management rather than immunosuppressive therapy for most patients with lymphoproliferation (eg, splenomegaly, lymphadenopathy, hepatomegaly) without autoimmune manifestations (Grade 2C). Patients with splenomegaly should use typical protective measures (eg, avoidance of contact sports due to risk of splenic rupture). (See 'Lymphoproliferation' above.)
Observation is preferred in most cases because adenopathy and organomegaly generally recede over time. Furthermore, when immunosuppressive therapy is used in these patients, lymphoproliferation typically returns after cessation of therapy. Similarly, tonsillar enlargement recurs after tonsillectomy.
However, immunosuppressive therapy is a reasonable alternative to observation in selected patients with isolated lymphoproliferation who have chronic symptoms that significantly compromise quality of life. The benefits of immunosuppression must be weighed against the side effects, particularly since lymphadenopathy and organomegaly return once immunosuppression is discontinued. If the decision is made to treat, we suggest mycophenolate mofetil (300 to 600 mg/m2/day) combined with a two- to three-week course of prednisone (1 to 2 mg/kg/day) rather than either agent alone or other agents (Grade 2C). (See 'Specific agents' above.)
•Lymphoma – Lymphoma is treated according to standard treatment protocols for the particular histologic type. Patients who develop lymphoma may be candidates for hematopoietic cell transplantation (HCT) because they have a high risk of relapse or second primary lymphoma after treatment. (See 'Curative therapy' above and "Overview of non-Hodgkin lymphoma in children and adolescents" and "Overview of Hodgkin lymphoma in children and adolescents".)
•Severe or recalcitrant disease – HCT is an option for patients with ALPS who have severe and recalcitrant autoimmune cytopenias, severe immunodeficiency during or after treatment, lymphoma, or a high-risk genotype (including patients with homozygous or compound heterozygous FAS defects and patients with additional genetic defects that complicate management). We recommend against splenectomy as a treatment for refractory autoimmune cytopenias or massive splenomegaly in patients with ALPS (Grade 1C). Splenectomy does not appear to achieve a lasting benefit and is associated with increased risk of death due to overwhelming sepsis in this population. (See 'Curative therapy' above and 'Avoidance of splenectomy' above.)
●Prevention of infections – Measures to prevent infections in patients with ALPS may include immune globulin replacement therapy and prophylactic antimicrobial therapy. Required immunizations should be administered prior to the institution of therapy, if possible. (See 'Avoidance of infections' above.)
●Prognosis – In many patients, lymphadenopathy and splenomegaly decrease in later childhood and adulthood and autoimmune features remain absent or manageable with limited need for immunosuppressive therapy. However, the prognosis is unpredictable and depends to some degree on the genotype, with some variants (eg, those affecting the intracellular domain of the Fas molecule and homozygous and compound heterozygous FAS pathogenic variants) generally having more severe disease and worse prognosis. (See 'Prognosis' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to earlier versions of this topic review.
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