Study of gene polymorphisms as predictors of treatment efficacy and toxicity in patients with indolent non-hodgkin lymphomas and mantle cell lymphoma receiving bendamustine and rituximab.

Bendamustine is used in combination with rituximab (BR) to treat indolent non-Hodgkin lymphomas (iNHL) and mantle cell lymphoma (MCL). The variability in treatment efficacy and toxicity could be related to single nucleotide polymorphisms (SNPs) in immune response genes. We would like to show a correlation between SNPs and treatment outcome in iNHL and MCL patients receiving BR. We investigated some SNPs that had already been associated with NHL outcome. Samples were genotyped for the IL2 (rs2069762), IL10 (rs1800890, rs10494879), VEGFA (rs3025039), IL8 (rs4073), CFH (rs1065489) and MTHFR (rs1801131) SNPs by allelic discrimination assays. We enrolled 70 patients that received rituximab 375 mg/m2 and bendamustine 90 mg/m2 every 28 days, both as first-line treatment and ≥ second-line regimens. Overall response rate was 97·1% (complete response [CR] rate 73·9%). Treatment toxicity included grade 3-4 neutropenia (24/70 patients), infections (21/70 patients; 1/70 grade 3), skin rash (26/70 patients; 2/70 grade 3). After a median follow-up of 24 months we did find any correlation between the analysed SNPs, CR rate and PFS. However, we demonstrated an association between the SNP in IL2 (rs2069762) and the onset of skin rash (P = 0·0001). Our study suggests a role for cytokine SNPs in bendamustine-related toxicity, which could represent a promising research field.

NK Cell Activation in the Antitumor Response Induced by IFN-α Dendritic Cells Loaded with Apoptotic Cells from Follicular Lymphoma Patients.

Follicular lymphoma (FL) is the most common form of indolent non-Hodgkin lymphoma. This malignancy is considered virtually incurable, with high response rates to therapy but frequent relapses. We investigated the ability of monocyte-derived dendritic cells generated in the presence of IFN-α and GM-CSF (IFN-DC) and loaded with apoptotic lymphoma cells to activate immune responses against FL cells, with the ultimate goal of designing novel patient-specific vaccination strategies for the treatment of FL. In this article, we show that apoptotic tumor cell-loaded IFN-DC from FL patients, which were cultured for 2 wk with autologous lymphocytes, led to Th1 response skewing, based on significantly higher levels of IFN-γ production and a remarkable increase in CD8(+) and NK cell frequency, consistent with the detection of enhanced cytotoxic effector function toward autologous FL cells. IFN-DC were found to promote efficient NK cell activation, increased expression of cytotoxicity receptors, and extensive IFN-γ production in the virtual absence of IL-10. Moreover, direct recognition and killing of primary autologous lymphoma cells by activated NK cells from FL patients was also demonstrated. A critical role was demonstrated for MHC class I-related chain A and B and membrane-bound IL-15 in IFN-DC-mediated NK cell activation and early IFN-γ production. The overall results indicate that IFN-DC loaded with autologous apoptotic FL cells represent a valuable tool for improving the potency of therapeutic cancer vaccines through the efficient induction of NK cell activation and promotion of CD8(+) T cell antitumor immunity.

Very long-lasting remission of refractory T-large granular lymphocytes leukemia and myeloma by lenalidomide treatment.

BACKGROUND: Large granular lymphocyte leukemias (LGLLs) represent a spectrum of biologically distinct lymphoproliferative diseases originating from either mature T cells (CD3+) or natural killer (NK) cells (CD3-). Both T-cell and NK-cell LGL leukemia can manifest as indolent or aggressive neoplasia. These rare lymphoproliferative disorders are often associated with autoimmune diseases and impaired hematopoiesis. Symptomatic patients are treated with immunosuppressive drugs. The co-association of T-LGLL with clonal B-cell disorders is reported in more than 10% of patients. CASE PRESENTATION: We describe the case of a 57-yr-old white male patient with no history of autoimmune disorders, with refractory T-LGLL and myeloma who was treated with bortezomib and subsequently with lenalidomide. After 30 months of on-going lenalidomide therapy, the patient is in partial remission from myeloma and in continuous complete hematological remission from T-LGLL. CONCLUSIONS: As far as we know, this is the first report of a patient with refractory T-LGLL treated with bortezomib and lenalidomide. As refractory T-LGLL is a challenging condition, we think that lenalidomide and bortezomib deserve further investigation.