How I treat autoimmune lymphoproliferative syndrome

Abstract

Autoimmune lymphoproliferative syndrome (ALPS) represents a failure of apoptotic mechanisms to maintain lymphocyte homeostasis, permitting accumulation of lymphoid mass and persistence of autoreactive cells that often manifest in childhood with chronic nonmalignant lymphadenopathy, hepatosplenomegaly, and recurring multilineage cytopenias. Cytopenias in these patients can be the result of splenic sequestration as well as autoimmune complications manifesting as autoimmune hemolytic anemia, immune-mediated thrombocytopenia, and autoimmune neutropenia. More than 300 families with hereditary ALPS have now been described; nearly 500 patients from these families have been studied and followed worldwide over the last 20 years by our colleagues and ourselves. Some of these patients with FAS mutations affecting the intracellular portion of the FAS protein also have an increased risk of B-cell lymphoma. The best approaches to diagnosis, follow-up, and management of ALPS, its associated cytopenias, and other complications resulting from infiltrative lymphoproliferation and autoimmunity are presented.

Trial registration: ClinicalTrials.gov NCT00001350.

Figures

Figure 1

Schematic diagram of current understanding of extrinsic and intrinsic apoptosis pathways. The prototypical receptor of the extrinsic pathway is FAS. It recruits the adaptor FADD and the procaspases 8 and 10 on ligation. The caspases are then cleaved to further activate other downstream caspases, leading to cell death. The intrinsic pathway is controlled by proteins of the BCL2 family and triggered by stimuli, such as DNA damage and growth factor withdrawal. These stimuli ultimately lead to activation of caspase 9 and downstream effecter caspases. There is a crosstalk between the 2 pathways in some cell types.

Figure 2

Signature biomarkers of ALPS-FAS. Biomarkers are very useful to predict the presence of FAS mutations in patients with features of ALPS. The increasing (A) or decreasing (B) post-test probabilities of having an FAS mutation in patients with different combinations of biomarkers.

Figure 3

CT and FDG-PET scans featuring ALPS-FAS–associated lymphadenopathy and splenomegaly. Patient 230 is a 10-year-old girl, with asymptomatic adenopathy and splenomegaly. Patient 232 is a 22-year-old man, with asymptomatic and visible cervical and axillary lymphadenopathy and modest splenomegaly. No intervention was indicated in both patients. Note the increased uptake in the spleen as a reflection of lymphoproliferation compared with liver in both patients.

Figure 4

More illustrative examples of FDG-PET and CT scan appearances of some ALPS-FAS patients show splenomegaly and lymphadenopathy. Patient 004 was a 25-year-old man who presented with fever, mouth ulcers, and neutropenia; suspected lymphoma was ruled out after these scans and biopsy of cervical lymph node. The patient underwent splenectomy for persistent cytopenias. Patient 072 was a 12-year-old asymptomatic boy with cervical and axillary adenopathy. Patient 161 was a 9-year-old boy treated with MMF for chronic cytopenias for the last 8 years; 3-dimensional CT reconstruction shows enlarged spleen with volume measured at 1972 cm3. Patient 317 is a 22-year-old man with splenomegaly; CT scan shows a spleen spanning 27 cm. Bottom panel: Chest CT scan appearance in a 19-year-old man (ALPS patient 109) with otherwise asymptomatic nodular lymphocytic pulmonary infiltrates. This patient has also been on therapy for his chronic cytopenias with MMF for the last 7 years.

Figure 5

Causes and consequences of splenectomy in a subset of 34 ALPS-FAS patients who have undergone long-term follow-up in our clinic. Note that more than half of them have relapsed with multilineage cytopenias after splenectomy requiring further therapeutic interventions, whereas one-third of them have had septic episodes.

Figure 6

Management suggestions for ALPS-associated chronic refractory cytopenias. This schematic diagram is included only as a suggested guideline for managing children with ALPS-associated autoimmune multilineage cytopenias. Use of G-CSF may be warranted for severe neutropenia associated with systemic infections. Similarly, use of other chemotherapeutic and immunosuppressive agents besides MMF and sirolimus (eg, hydroxychloroquine, methotrexate, mercaptopurine, vincristine, azathioprine, and cyclosporine) can also be considered as a steroid-sparing measure or used while avoiding or postponing surgical splenectomy at the discretion of the treating clinicians based on the circumstances of a specific patient.