PF351 ALPS DISEASE AND ALPS PHENOTYPE: DISTINCT ENTITIES?

Background: Autoimmune lymphoproliferative syndrome (ALPS) defined according to the clinical/biochemical criteria (NIH 2009) is known to be mainly caused by FAS, FASL, FADD and CASP10 gene mutations. Nevertheless, several patients carrying a clear ALPS phenotype are not associated with these mutations Aims: Describe the clinical, biochemical and therapeutic characteristic in ALPS patients with and without the classical mutations and correlate them with genetics. Methods: The demographic, clinical, biochemical, genetic informations and details about treatment are derived from the ALPS Italian Network. Search of mutations was performed with Sanger PCR and/or Next Generation sequencing techniques (extended to immunodeficiency genes panel). Results: Among 68 ALPS patients registered in the data base (Males, 60%), 42 subjects (62%) received a genetic definition: 14 pts (33%) carried classical mutations in FAS/CASP genes, 16 pts (37%) showed mutation in genes other than FAS/CASP (LRBA, STAT, CTLA4, CECR, BAFF, TACI, RAG, NEMO, IKBKG, Gaucher) and 12 pts (28%) were negative for FAS/CASP. Clinical phenotype in the two groups appeared rather different being “more complex“ in the ALPS FAS negative group if compared with the FAS/CASP one. (p = 0.003) (Table 1).The multi‐organ involvment was often associate with positivity of autoimmune markers (p = 0.002) (Table 1). Cytopenia affecting one or more haematopoietic lineages was present in both groups (69% and 82%) without difference; while leucopenia/lymphocytopenia was shown more frequently in FAS/CASP mutated group rather than in the ALPS FAS negative one (p = 0.03) (Table 1). As for lymphocyte subclasses and immunoglobulin dosage no differences were shown within the two groups. Vitamin B12 and IL‐10 were more frequently raised in ALPS FAS/CASP mutated group than in the non mutated FAS/CASP genes (p = 0.01, p = 0.001). Four of 42 (9%) patients did not require any treatment, while the remaining 38 received one or more lines or drug combinations. First line treatment (steroid or intravenous immunoglobulins) controlled the disease in 4/38 (10%). In the ALPS FAS/CASP POS group response rate to second line treatment (mostly MMF and rapamycin) was 100%, while in the ALPS FAS/CASP negative group MMF and rapamycin were not able to control symptoms in the majority of subjects (response rate 40%). Drug combinations or target therapies were more commonly applied in patients belonging to FAS/CASP negative group rather than in the ALPS FAS/CASP POS group (p = 0.002, p = 0.02) (Table 1). Summary/Conclusion: Patients carryng ALPS phenotype without FAS or CASP mutations probably represent a distinct entity as compared to those with classical ALPS phenotype and genotype regarding clinical appearance, biochemical characteristic and genetic pattern. Moreover genes frequently associated with immunodeficiency/disimmunity patterns are more represented in FAS/CASP negative group. These findings are relevant for therapeutic management, especially in the cases when target therapies are available. In ALPS FAS/CASP POS group, MMF or rapamycin are highly effective to manage disease. Their use would allows steroid‐sparing strategy and in some cases should be proposed even as a first line choice.