High-throughput Proteomics Identifies THEMIS2 as Independent Biomarker of Treatment-free Survival in Untreated CLL.

It remains challenging in chronic lymphocytic leukemia (CLL) to distinguish between patients with favorable and unfavorable time-to-first treatment (TTFT). Additionally, the downstream protein correlates of well-known molecular features of CLL are not always clear. To address this, we selected 40 CLL patients with TTFT ≤24 months and compared their B cell intracellular protein expression with 40 age- and sex-matched CLL patients with TTFT >24 months using mass spectrometry. In total, 3268 proteins were quantified in the cohort. Immunoglobulin heavy-chain variable (IGHV) mutational status and trisomy 12 were most impactful on the CLL proteome. Comparing cases to controls, 5 proteins were significantly upregulated, whereas 3 proteins were significantly downregulated. Of these, only THEMIS2, a signaling protein acting downstream of the B cell receptor, was significantly associated with TTFT, independently of IGHV and TP53 mutational status (hazard ratio, 2.49 [95% confidence interval, 1.62-3.84]; P < 0.001). This association was validated on the mRNA and protein level by quantitative polymerase chain reaction and ELISA, respectively. Analysis of 2 independently generated RNA sequencing and mass spectrometry datasets confirmed the association between THEMIS2 expression and clinical outcome. In conclusion, we present a comprehensive characterization of the proteome of untreated CLL and identify THEMIS2 expression as a putative biomarker of TTFT.

Adalimumab-induced platelet antibodies resulting in severe thrombocytopenia.

Anti-tumour necrosis factor-α (TNFα) agents are effective in diseases including Crohn's disease but may cause cytopenias. The mechanisms involved in anti-TNFα agent-induced thrombocytopenia are scarce. We report a 73-year-old male with Crohn's disease for which he currently used adalimumab, an anti-TNFα agent. He had received mesalazine and infliximab before the treatment of adalimumab. No comorbidities were present. Routine laboratory tests revealed a deep thrombocytopenia (thrombocytes 24 × 109 /L), after which adalimumab was discontinued. Bleeding symptoms included cutaneous haematomas and mild epistaxis. Direct monoclonal antibody-specific immobilization of platelet antigens revealed autoantibodies specific to glycoprotein IIb/IIIa and glycoprotein V platelet receptors. There was no bone marrow suppression. Other causes of the thrombocytopenia were ruled out. The platelet count normalized after adalimumab discontinuation. No further interventions were required. Monitoring thrombocyte levels after initiating anti-TNFα agents is recommended, which could lead to prevention of this potentially fatal phenomenon.