Autoimmune cytopenias (AIC) affect 5-9% of patients with chronic lymphocytic leukemia (CLL). Targeted drugs - ibrutinib, idelalisib and venetoclax - have a prominent role in the treatment of CLL, but their impact on CLL-associated AIC is largely unknown. In this study, we evaluated the characteristics and outcome of pre-existing AIC, and described the incidence, quality and management of treatment-emergent AIC during therapy with targeted drugs in patients with CLL. We collected data from 572 patients treated with ibrutinib (9% in combination with an anti-CD20 monoclonal antibody), 143 treated with idelalisib-rituximab and 100 treated with venetoclax (12% in combination with an anti-CD20 monoclonal antibody). A history of pre-existing AIC was reported in 104/815 patients (13%). Interestingly, 80% of patients whose AIC was not resolved at the time of targeted drug start experienced an improvement or a resolution during therapy. Treatment-emergent AIC occurred in 1% of patients during ibrutinib therapy, in 0.9% during idelalisib and in 7% during venetoclax, with an estimated incidence rate of 5, 6 and 69 episodes per 1000 patients per year of exposure in the three treatment groups, respectively. The vast majority of patients who developed treatment-emergent AIC carried unfavorable biological features such as an unmutated IGHV, and a del(17p) and/or TP53 mutation. Notably, despite AIC, 83% of patients were able to continue the targeted drug, in some cases in combination with additional immunosuppressive agents. Overall, treatment with ibrutinib, idelalisib and venetoclax appears to have a beneficial impact on CLL-associated AIC, inducing an improvement or even a resolution of pre-existing AIC in most cases and eliciting treatment-emergent AIC in a negligible portion of patients.

Purpose of review This review provides guidance in the rapidly changing scenario of chronic lymphocytic leukemia (CLL) treatment. New studies as well as updates of other seminal ones have been recently presented and are likely to change the management of patients with CLL in everyday clinical practice. Recent findings Kinase inhibitors (e.g. ibrutinib and idelalisib) have transformed the treatment paradigm in CLL in both front-line and relapsed/refractory patients. Longer follow-up data are now available supporting the safety of ibrutinib and the continuous administration required per current label. Novel studies show the superiority of the drug alone or in combination with monoclonal antibodies compared with standard chemoimmunotherapy. The combination of venetoclax and obinutuzumab (treatment-naïve, only in United States) or rituximab (relapsed/refractory) has granted approval from the regulatory authorities in United States and Europe, based on phase 3 randomized studies. These novel chemo-free combinations allow for fixed-duration treatment and undetectable minimal residual disease. Novel targeted strategies including second and third generation BTK and PI3K inhibitors are currently under investigation and promise to further improve the CLL treatment armamentarium. The chimeric-antigen receptor (CAR) T cells are coming to the stage with promising efficacy and new challenges. Summary A bright chemo-free era for CLL patients is just around the corner. A deep knowledge of currently available evidences is key to tailor treatment choice and optimize long-term tolerability and disease control. Fixed-duration combinations are investigated to allow treatment holidays and avoid the emergence of resistant clones under the selective pressure of continuous treatment.

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the BCR signaling-related molecule, phosphorylated form of SYK (pSYK), were immunohistochemically evaluated on formalin-fixed, paraffin-embedded tumor tissues. The expression status of LMP2A, pSYK and BCR were further validated by a flow cytometry analysis using fresh tissues from 3 EBV-positive and 5 EBV-negative DLBCL patients.Results: The EBV-positive cases, with a median age of 61yrs, were more frequently associated with a high-risk IPI score and a non-GCB phenotype (P=0.029). Compared with EBV-negative ones, patients with EBV-positive tumors showed a worse response to the RCHOP therapy and a shorter median survival (P = 0.041). Twenty-one EBVpositive cases (75 %) expressed LMP2A, whereas none of the EBVnegative cohort expressed this protein. The expression level of pSYK was significantly lower (P = 0.0313) in EBV+ DLBCL cases than those EBV-negative ones, and the pSYK level correlated negatively with LMP2A level (P = 0.119). The expression level of PD-L1 was significantly higher (P = 0.042) in EBV+ DLBCL, which correlated positively with the LMP2A level (P=0.184). Flow cytometry confirmed the LMP2A expression in EBV+ DLBCL, which correlated with a downregulated BCR and pSYK expression.Conclusions: EBV+ DLBCL seems to feature an inactive BCR signaling, which may be related to the expression of LMP2A.Besides, LMP2A may function and promote the PD-L1 expression.These findings indicate that targeting immune checkpoints including PD-1/PD-L1 instead of BCR signaling molecules seems to be more reasonable and promising for the treatment of EBV+ DLBCL. ABSTRACT Introduction: diffuse large B-cell lymphoma (DLBCL) represents the most common subtype of non-Hodgkin lymphomas (NHLs).Standard chemoimmunotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) is able to cure a significant proportion of patients; however, 30% of total cases experience relapse or have refractory disease. The international prognostic index (IPI) represents the most useful prognostic score, but it is exclusively based on clinical parameters. Previous studies showed the microenvironment has a prognostic influence in DLBCL cases; among its cellular components, tumor-associated macrophages (TAM) surely play a leading role. TAM can be classified into 2 distinct types, M1 (anti-tumor activity) and M2 (protumor activity). Another prognostic factor could be represented by lymphopenia, measured as lymphocyte-to-monocyte and neutrophil-to-lymphocyte ratio (LMR and NLR), that reflects a reduced host systemic immunity.Methods: in this study we would like to evaluate the prognostic impact of total TAM, M1 and M2 subtypes, LMR and NLR in newly diagnosed DLBCL patients. The primary objective is represented by progression-free survival (PFS). Secondary objectives are complete remission (CR) rate and overall survival (OS). We have retrospectively analyzed a cohort of 37 consecutive newly diagnosed DLBCL patients, treated between 2009 and 2013. Out of 37 patients, 28/37 (75.6%) received R-CHOP or CHOP-like regimens, 9/37 (24.4%) ...