26/7/2017 Autoimmune lymphoproliferative syndrome (ALPS): Management and prognosis - UpToDate

Cerrar Sesin

Author: Jack JH Bleesing, MD, PhD

Section Editor: Jennifer M Puck, MD
Deputy Editor: Elizabeth TePas, MD, MS

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jun 2017. | This topic last updated: Jan 13, 2017.

INTRODUCTION Autoimmune lymphoproliferative syndrome (ALPS) is a rare primary immune disorder

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).

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".)

MANAGEMENT Management of ALPS focuses upon three aspects: treatment of disease manifestations,
treatment/prevention of complications arising from the disease and its treatment, and curative therapy [1,2].
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. The development of autoimmune
disease changes the therapy needed as well as the prognosis.

Evaluation and monitoring following initial diagnosis The presence and extent (disease
manifestations and disease burden) of lymphoproliferation and/or autoimmunity should be determined
before initiating therapy in an individual newly diagnosed with ALPS or suspected to have ALPS.

This can be achieved with a combination of physical examination, imaging studies (eg, computed
tomography [CT] scan and/or positron emission tomography [PET] scans) of body areas thought to be
involved (typically neck, chest, abdomen, and pelvis), and 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, Fas ligand [FasL]), blood counts, and the presence and nature of
autoantibodies (eg, directed against blood cells). In patients deemed to need immunosuppressive therapy,
one should also initiate a basic investigation of the integrity of immune system, particularly in young
patients. (See "Laboratory evaluation of the immune system".)

This evaluation should also include an assessment for lymphoma in patients with extensive
lymphadenopathy, especially those with constitutional symptoms (eg fever, weight loss, night sweats). PET
imaging may be helpful in this regard since it is often difficult to distinguish between benign (ALPS-specific)
lymphadenopathy and malignant lymphoma that may be present concomitantly. PET scans can direct the
surgeon to the node or nodes with high metabolic activity that are most likely to be of diagnostic value.
Investigation for lymphoma is particularly important if immunosuppressive and/or immunomodulating agents
are contemplated since lymphoma development may be altered and/or masked by the use of these agents.

There is some evidence to suggest that periodic surveillance using combined anatomical (ie, CT scan) and
functional/metabolic (ie, PET scan) imaging may be helpful, although more long-term data collection is
needed to determine the cost-to-benefit ratio of expensive imaging [3].

Many laboratory findings, including the number of DNT cells and amounts of IL-10, FasL, and other
biomarkers, not only serve a diagnostic purpose but also can be used to monitor disease activity and
response to therapy.

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Whether the patient needs to be treated and, if so, with which agent or agents, is determined following this
evaluation. If the decision is made not to initiate treatment, periodic follow-up is recommended using the
tools described above.

Treatment of disease manifestations The management of disease manifestations is focused on the

control/treatment of lymphoproliferation and/or autoimmunity and the treatment of lymphoma [2,4-9].
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.

Once initiated, immunosuppressive and/or immunomodulating therapy may be difficult to stop, which should
be taken into consideration because of the side effects, risks, and cost of long-term immunosuppressive
treatment. The development of symptomatic autoimmune cytopenias often indicates a new phase in the
course of ALPS in a particular patient. Therapies that affect the immune system cannot be used for
extended periods of time (years), particularly in children, without 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 renal
impairment. In addition, the immune system may not tolerate suppression for prolonged periods of time.
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 and acquire common viral
infections, such as those due to cytomegalovirus (CMV) and Epstein-Barr virus (EBV). (See "Major side
effects of systemic glucocorticoids" and "Secondary immunodeficiency induced by biologic therapies".)

Lymphoproliferation Manifestations of lymphoproliferation can be suppressed by the use of

immunosuppressive agents, such as glucocorticoids, cyclosporine, sirolimus, tacrolimus, or mycophenolate
mofetil [4,10,11]. The benefits of immunosuppression, however, are balanced by the side effects, and
therapy is generally not required for lymphoproliferation in the absence of autoimmunity. In addition,
lymphadenopathy as well as splenomegaly and/or hepatomegaly return once immunosuppression is
discontinued [4]. Thus, we suggest use of immunosuppressive therapy only for severe complications of
lymphoproliferation (eg, airway obstruction by enlarged tonsillar tissue or cervical adenopathy, massive
splenomegaly) and/or in the presence of concomitant autoimmune manifestations that require therapy.

Mycophenolate mofetil is typically well tolerated and requires little monitoring, making it our preferred agent
with which to start therapy. It appears to induce modest improvement in lymphadenopathy and some
improvement in splenomegaly (in some patients) and laboratory markers, such as lymphocyte counts and
IL-10 and vitamin B12 levels. Dose and duration of therapy should be individualized to the patient. It is
reasonable to determine 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 [11]. This is balanced by the fact that sirolimus requires
monitoring of levels, side effects, and complications, including infections. On the other hand, it is less
mutagenic than mycophenolate mofetil, tacrolimus, and cyclosporine [12]. In addition, long-term use of
calcineurin inhibitors (eg, tacrolimus, cyclosporine) is associated with renal toxicity [13].

The author's approach is to determine if therapy is needed, based upon considerations discussed above.
The author starts with the least immunosuppressive agent to accomplish treatment goals, particularly if
long-term immunosuppression beyond a few weeks is needed. In most patients, this can be achieved with
mycophenolate, with or without a short course (approximately two to three weeks) of prednisone. The
author uses clinical response, 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). In patients with insufficient response to mycophenolate, concomitant (or new) autoimmunity, or
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mycophenolate intolerance, the author reaffirms the necessity of long-term immunosuppressive therapy
and, if indicated, initiates sirolimus, starting with a dose to keep drug levels at the lower end of the
therapeutic range.

Splenectomy is not recommended in patients with ALPS, due to the reported lack of sustained therapeutic
benefit and increased incidence of postsplenectomy sepsis in both children and adults. In the French ALPS
cohort, 33 percent of 90 patients underwent splenectomy (40 percent for massive splenomegaly and 60
percent for refractory autoimmune cytopenias) [14]. In the National Institutes of Health (NIH) ALPS cohort,
44 percent of 150 patients needed splenectomy, three-quarters for refractory cytopenias that typically
involved more than one lineage [15]. 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 at 4 and 20 years
postsplenectomy, 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
[14,15]. 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 found to be a risk factor for sepsis postsplenectomy. Antimicrobial prophylaxis and
appropriate vaccinations did not prevent the majority of the episodes of sepsis, although poor compliance
was found to be a risk factor in the French cohort.

Autoimmune manifestations Autoimmune manifestations typically respond to immunosuppressive

agents. 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. Patients with autoimmune manifestations typically have a more difficult time
coming off of immunosuppressive therapy than patients with lymphoproliferation only.

Mycophenolate mofetil, cyclosporine, tacrolimus, and particularly sirolimus are effective in chronic
recalcitrant autoimmune cytopenias and may enable weaning or avoidance of glucocorticoids [9,11,16].
A multi-institutional, prospective study demonstrated efficacy of sirolimus monotherapy in ALPS [17].
Patients achieved a durable complete response, including rapid improvement in autoimmune disease,
lymphadenopathy, and splenomegaly within one to three months of starting sirolimus.

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. Transition to steroid-sparing
agents is undertaken as glucocorticoid doses are tapered [2].

Rituximab has been used successfully in the treatment of refractory cytopenias in ALPS, although it is
not yet known how long affected individuals will remain in clinical remission [9,18]. Experience suggests
that monitoring B cell reconstitution following rituximab may help with estimating duration of remission
and also with determining possible hypogammaglobulinemia post-rituximab. In patients with ALPS who
are asplenic, drug-related adverse effects, including hypogammaglobulinemia and rituximab-induced
neutropenia, may add to the infection risk burden [19].

High-dose intravenous immune globulin (IVIG) is sufficient to control cytopenias in some patients [4].

Severe (recalcitrant) cytopenias or other potentially life-threatening autoimmune manifestations may

require the use of plasmapheresis in combination with other modalities, including bortezomib [20].

The author's approach is to use a combination of immunosuppressive and immunomodulating agents.

Depending upon severity, this can be high-dose IVIG, a course of prednisone, and initiation of a T cell agent
(eg, mycophenolate), if necessary switching to a more potent T cell agent (eg, from mycophenolate to
sirolimus or tacrolimus). If high-dose IVIG does not achieve/maintain remission (which is commonly the

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case in ALPS), the author uses rituximab as the immunomodulating agent, keeping in mind that the patient
will generally require immune globulin replacement secondary to development of hypogammaglobulinemia.

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.

Prevention of complications Most complications are the results of immunosuppressive and

immunomodulating agents and relate to the increased risk of infections or systemic side effects of
glucocorticoids. Intravenous or subcutaneous immune globulin therapy is warranted in some cases, as well
as antimicrobials to prevent opportunistic, fungal, and viral infections. Infections caused by
immunosuppressive and immunomodulating agents need to be thoroughly investigated with cultures and
aggressively treated. (See "Secondary immunodeficiency induced by biologic therapies".)

In patients who have had a splenectomy, lifelong penicillin prophylaxis is strongly recommended, and
postsplenectomy booster vaccinations are suggested. (See "Prevention of sepsis in the asplenic patient".)

Curative therapy Hematopoietic cell transplantation (HCT) is the only curative treatment for ALPS
[21,22]. Reduced-intensity preparative regimens offer lower morbidity and mortality than myeloablative
preparative regimens and have been used successfully in primary immunodeficiencies. Our treatment
protocol includes alemtuzumab, fludarabine, and melphalan as the reduced-intensity regimen. This
conditioning regimen is well tolerated [23]. The status of ALPS disease activity needs to be carefully
evaluated, and the potential consequences of long-term treatments, including organ function, need to be
compared with the risks of transplantation before HCT is performed.

Examples of transplant indications include:

Lymphoma development because of the potential for relapse or second primary lymphoma after
therapy.

Severe and recalcitrant autoimmune cytopenias, with disease manifestations that can be controlled
only by aggressive and sustained immunosuppression.

Development of a significant immunodeficiency disorder during or following prolonged

immunosuppressive therapy.

Patients with a severe disease phenotype at the time of diagnosis, including, but not limited, to patients
with homozygous and compound heterozygous FAS defects. This may also pertain to patients with
complex genotypes, in which an additional genetic defect complicates management [24,25].

Recurrent severe invasive bacterial infection or sepsis postsplenectomy despite adequate antimicrobial
prophylaxis and appropriate vaccinations [26].

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 mutations (ALPS-sFAS) did not inherit the genetic defect in FAS
from either of the parents and do not appear to carry the mutation in their germline DNA. Consequently,
their offspring will not inherit the somatic mutation. In contrast, those with a constitutional mutation are at 50
percent risk of passing the mutation 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.

PROGNOSIS Many patients with ALPS have a favorable prognosis, with lymphadenopathy decreasing
over time and autoimmune features remaining absent or manageable with limited need for
immunosuppressive therapy. Some patients with particular mutations 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

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will follow, regardless of the genotype. Thus, long-term follow-up is indicated for the majority of patients to
follow and try to anticipate the course of each individual's disease. A significant component of follow-up care
should focus on education and empowerment of patients and their families. 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 [27].

Patients with mutations in FAS that affect the extracellular domains, particularly if these mutations cause
defective apoptosis through haploinsufficiency (rather than dominant-negative interference), may have less
severe disease and/or be less at risk for lymphoma development. This optimism needs to be balanced with
the recognition of second genetic hits affecting FAS [27].

Patients with homozygous and compound heterozygous FAS mutations have very early onset, severe
manifestations, and a worse prognosis that typically requires allogeneic bone marrow transplantation 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.

SUMMARY

Autoimmune lymphoproliferative syndrome (ALPS) is a rare disorder characterized by defective

lymphocyte homeostasis, resulting from defective Fas-mediated apoptosis. (See 'Introduction' above
and "Autoimmune lymphoproliferative syndrome (ALPS): Epidemiology and pathogenesis".)

Management of ALPS focuses upon three aspects: treatment of disease manifestations, prevention
and treatment of complications, and curative therapy (hematopoietic cell transplantation [HCT]). (See
'Management' above.)

We suggest use of immunosuppressive therapy only for severe complications of lymphoproliferation

(eg, airway obstruction) and/or in the presence of concomitant autoimmune manifestations (Grade 2C).
Splenectomy is not recommended for autoimmune manifestations in patients with ALPS, due to the
reported lack of sustained therapeutic benefit and increased incidence of life-threatening
postsplenectomy sepsis. (See 'Treatment of disease manifestations' above.)

HCT is reserved for selected patients, such as those with lymphoma or severe recalcitrant disease.
(See 'Curative therapy' above.)

Many patients with ALPS have a favorable prognosis, with lymphadenopathy decreasing over time and
autoimmune features remaining absent or manageable with limited need for immunosuppressive
therapy. (See 'Prognosis' above.)

ACKNOWLEDGMENT The editorial staff at UpToDate would like to acknowledge E Richard Stiehm, MD,
who contributed as a Section Editor to an earlier version of this topic review.

Use of UpToDate is subject to the Subscription and License Agreement.

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