In conclusion describing a single case

In conclusion, describing a single case observation of a PV-patient we have for the first time delivered the “proof of concept” that combination therapy with Rux and “low-dose” IFN is safe, tolerable and highly efficacious in PV, as evidenced by a rapid reduction in the JAK2V617F-allele burden in concert with normalization of blood counts and resolution of pronounced splenomegaly and constitutional symptoms. This observation warrants prospective trials of this combinatorial approach in patients with PV and hyperproliferative MF to assess, if combination therapy induces a more rapid decline in the JAK2V617F-allele burden compared to monotherapy with either drug. In addition, studies are urgently needed to elucidate, if combination therapy – by alleviating potential side effects of IFN, which otherwise might disqualify for further IFN- treatment, might actually rescue IFN-intolerant or IFN-non-responsive patients, thereby improving their quality of life and likely maintaining the goal of achieving major molecular remission and hopefully “minimal residual disease” as well [1,2,9,10].
Acknowledgments All authors contributed to the writing and editing of the article. Hans Hasselbalch has received a research Grant from Novartis. Novartis had no knowledge regarding this case report and consequently had no influence on the manuscript.
Introduction Multiple myeloma (MM) is a plasma cell neoplasm characterized by the production of a monoclonal protein, bone destruction and susceptibility to infections [1,2]. Most infections in myeloma patients are caused by bacteria, and this susceptibility to infection is mostly due to the reduction in the production of normal immunoglobulins, typical of the disease [3]. The conditioning regimen for the autologous stem cell transplantation (ASCT) further increases patient׳s vulnerability to infections [1]. High levels of proinflammatory cytokines such as IL-6 and TNF-α are related to MM pathogenesis, and have a relationship with the immune response and the susceptibility to infections. Single nucleotide polymorphisms (SNPs) in the promoter region of cytokines ciprofloxacin are responsible for altering their levels of expression, thereby affecting the immune response [1,3,4]. Specifically, the SNP −174G>C (rs1800795) has been correlated with higher levels of IL-6 [5], and the −308G>A (rs1800629) is associated with higher serum levels of soluble TNF-α [6]. These SNPs have been previously studied in multiple myeloma [4,6]. However, gene–gene interactions have been successfully used to detect susceptibility to complex diseases, and it is possible that gene interactions may influence the outcome in patients with multiple myeloma [7,8]. Therefore, we aimed to evaluate the association of these SNPs with bacteremia in MM patients submitted to ASCT. Moreover, as IL-6 and TNF-α cytokines are known to biologically interact in immune response pathways, we also performed gene–gene interaction analyses between these SNPs.
Material and methods All patients received melphalan-based conditioning regimen and peripheral blood stem cells (PBSC) after mobilization with granulocyte colony-stimulating factor (G-CSF) with or without cyclophosphamide. Until 2006, no antibacterial prophylaxis had been given. Since then, all patients received ciprofloxacin (500mg orally twice a day), started concomitantly with the conditioning regimen, and was maintained until bone marrow recovery or fever. In case of fever, blood cultures were obtained, and the patients were immediately started on intravenous cefepime Blood cultures were repeated in case of persistent or recurrent fever, or as clinically indicated. Modifications in the empirical antibiotic regimen were performed according to the results of cultures and the clinical course of the patient. Genomic DNA was extracted from mobilized peripheral-blood stem cells. Genotyping was carried out for the SNPs IL-6 (–174G>C) and TNF-α (–308G/A) using PCR followed by restriction length fragment polymorphism (PCR-RFLP). Clinical and genotypic database and genotypic analysis were performed with the Statistical Package for the Social Sciences version 15 (SPSS Inc., Chicago, Ill), using the Chi-square test. The gene–gene interaction analysis was performed by multifactor dimensionality reduction (MDR) method [8]. We used MDR to combine multilocus genotypes into high risk and low risk cells, which were evaluated for the ability to predict bacteremia through cross-validation and permutation testing. We considered as the best model of interaction the one that had the maximum testing accuracy and the maximum cross-validation consistency (CVC). Permutation testing was performed to assess the statistical significance of the testing accuracy of the best model [8]. Bivariate analysis (logístic regression) was performed to evaluate the impact of the use of quinolones on the risk of bacteremia.