Specific Anti-Nuclear Antibodies, Clinical Features and Outcome Following Treatment with Nilotinib In Patients with Chronic Graft-Versus-Host Disease. The 44th Annual Meeting of the European Society for Blood and Marrow Transplantation: Physicians Poster Sessions

Background: Clinical manifestations of chronic graft versus-host diseases (cGVHD) often resemble systemic autoimmune diseases. The association with autoantibodies, including anti-nuclear antibodies (ANA), has been reported, but the clinical and prognostic relevance of this association is still unclear. Tyrosine kinase inhibitor nilotinib is currently under investigation for the treatment of cGVHD; we sought to investigate the relationship between presence of ANA and outcome of cGVHD following administration of nilotinib. Methods: Fifteen patients with severe cGVHD following hematopoietic stem cell transplantation (HSCT) and nine transplanted patients without cGVHD (controls) were evaluated. Clinical data were collected by patients´ files. A panel of 19 specific ANA was assessed by quantitative immunoblot assay (Alifax, Padova, Italy). Proportions of T cell subpopulations (including T helper, T cytotoxic and T regulatory), B lymphocytes, NK and NK/T cells were assessed by flow cytometry (Bekton Dickinson, San Josè, CA). Data were compared by Student´s t test; differences were considered statistically significant when p < 0.05. Results: In patients who developed cGVHD, organs more commonly involved were skin (80%), eyes/mouth (Sicca Syndrome, 67%) and lungs (33%); ANA were detected in seven of these patients (47%, figure panel A). Most frequent specificity was anti-SSA/Ro (3 cases); other specificities were anti-SSB, anti-CENP A/B, anti-Nucleosome and anti-Pm-Scl (1 case each). Sicca Syndrome was the clinical manifestation more associated with the presence of ANA (7/10 cases, 70%), followed by skin disease (5/12 cases, 42%). Only one of the controls (11%) was tested ANA-positive (anti Histones/PCNA/DFS-70, figure panel A); of note, this patient suffered from isolated xerostomia. No difference in timing of cGVHD onset following HSCT was observed between ANA-positive and ANA-negative patients (267 vs. 280 days, p = 0.88). Compared to controls (figure panels BE), cGVHD patients had significantly higher proportions of T and NK/T cells (p < 0.05) and lower proportions of B (p=0.06) and NK cells (p < 0.05). CD4/CD8 ratio (not shown) as well as T regulatory cells (figure panel F) were comparable between the two groups; however, this latter subset showed a trend toward higher values among ANApositive compared to ANA-negative cGVHD patients (10,7±7.9% vs. 3.4±1.4%, p = 0.12). No difference in cGVHD progression nor in response to nilotinib was observed between ANA-positive and ANA-negative patients; after six months of treatment, eight (4 ANA-positive) remained stable and the other seven (3 ANA-positive) improved. Conclusions: In agreement with published data, presence of ANA was frequent among patients who developed cGVHD and uncommon among transplanted patients without this condition. Most common cGVHD clinical features were skin disease and Sicca Syndrome; the latter was also the most frequent manifestation among ANA-positive cGVHD individuals. Although the frequency of B cells was not increased among patients developing cGVHD, these data suggest that B cells may play a pathogenic role in the onset of this condition and that presence of ANA may predict the development of particular clinical manifestations, such as Sicca Syndrome. Six-months course of nilotinib stabilized or improved cGVHD in all the study patients, independently of the presence of ANA. The evaluation of autoantibodies and immune population after nilotinib treatment is ongoing.