Hematologic patients are at greater risk of developing second primary malignancies, due to their immune impairment, caused by the immunosuppressive factors they produce, but also to the lymphoma treatment. According to some studies, a history of chemotherapy is a risk factor for the development of BCC [
2]. The gold standard treatment is surgical excision, but in older people, patients with multiple lesions and transplanted patients, the medical approach is to be preferred. The most used topical therapies are imiquimod and 5-fluorouracil. Most cases are treated with imiquimod rather than surgically, as it has been shown that the drug acts also on the cancerization field, as demonstrated by the reduced risk of subsequent BCC in treated patients [
11]. Imiquimod is an immune response modifier, which acts as a TLR-7 agonist. TLRs usually recognize pathogens and activate the releasing of inflammatory cytokines. In fact, TLR-7 triggers the transcription factor NF-kappaB, promoting the production of proinflammatory cytokines and other inflammatory mediators. This function leads to the activation of APCs and stimulation of an important Th
1 antitumoral cellular immune response. Moreover, at higher concentrations, imiquimod causes a proapoptotic activity against tumor cells. This involves caspases activation and apparently depends on Bcl-2 proteins. This family of antiapoptotic proteins controls mitochondrial permeability. Imiquimod induces a reduction of Bcl-2 protein expression and, consecutively, an increase of the apoptotic index of the BCC cells [
6]. Finally, it has been recently demonstrated that imiquimod acts directly on BCC by inhibiting Hedgehog signaling, given that this skin cancer is Hedgehog-driven [
12]. The combination of all these activities explains the antitumoral action of imiquimod. In our two patients, previously treated with R-CHOP, we observed a reduced efficacy of imiquimod. This drug is used due to its effect on T cell activation, on increasing natural killer (NK) cells and on APC functions as well as against other tumors. Its efficacy has been demonstrated on cutaneous lymphomas (mycosis fungoides) [
13]. Therefore, we speculate a likely effect of previous treatment with RTX on T cells. RTX acts specifically on CD20, expressed on B lymphocyte membrane with a transient effect on a particular population of T cells. This subpopulation expresses CD20 surface antigen, as well as CD3. They represent a pool of constitutive activated T cells, which produce and release a high quantity of proinflammatory cytokines [
14]. Moreover, we also studied and determined the effect of RTX on the most important APCs, the dendritic cells (DCs). Apart from morphology change, there was a lower expression of some surface antigens (HLA-DR, CD80, CD83, CD86, IL-12p70) involved in antigen presentation, stimulating proliferation and inhibiting T cells apoptosis. Transforming growth factor beta 1 (TGF-beta1) increased, thus causing the inhibition of T cell action, preventing proliferation of activated T lymphocytes/activation of quiescent helper or cytotoxic T cells and the secretion of proinflammatory cytokines [especially interferon-gamma (IFN-gamma) and interleukin-2 (IL-2)]. All these mechanisms reflect a reduced ability to activate T cells by DCs [
15]. We also saw a transient, dose-dependent T cell inactivation after RTX administration. Their responsiveness to DCs reduced remarkably during treatment, as shown by the higher risk of T cell-dependent infectious diseases that then reduces a few months after the end of the therapy [
16]. We suppose that RTX is the cause of the lack of response to imiquimod in these patients, because CHOP has been demonstrated to cause reversible peripheral blood cytopenia. On the other hand, RTX reduces the function, as well the count of peripheral blood and DCs. RTX most likely decreases the host immune response making patients anergic toward topical immune stimulation by imiquimod. Besides B cell depletion, that could reflect the transient reduced activation of T cells, RTX acts on T cells in different ways. Despite its direct functioning on CD20+ T cells, this is only transient. The most likely mechanism of action of RTX could be due to its action on DCs. In fact, patients with an important reduction of T cell activation and functioning could develop typical T cell-dependent infectious diseases.