Poster Session I: Bone marrow failure syndromes incl PNH - Clinical
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
Describe the clinical, biochemical and therapeutic characteristic in ALPS patients with and without the classical mutations and correlate them with genetics.
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).
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).
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.