Novel therapeutics in hairy cell leukemia.

Introduction: Hairy Cell Leukemia (HCL) is an indolent lymphoproliferative disorder resulting in a high complete response rate when treated with purine nucleoside analogs. However, at some time, nearly all patients relapse. In the relapsed setting, historically, options beyond repeat treatment with a purine nucleoside analog were limited. A number of novel agents have now been prospectively studied clinically for HCL in this setting.Areas covered: A review of the prospective data on newer agents in the relapsed setting is discussed. Emphasis is placed on overall response rates, complete response rates, minimal residual disease rates, and toxicities. The drugs vemurafenib, moxetumumab-pasudotox, bendamustine, and ibrutinib, all of which are commercially available, are reviewed in greatest detail.Expert opinion: Despite the number of prospective studies recently published on these agents in HCL, questions remain about which agents to use, when to best utilize them, how to best dose or schedule them, and the role of combination therapy. Further clinical research is required to answer these questions and to discover other drugs effective in the treatment of relapsed HCL.

Current Therapy and New Directions in the Treatment of Hairy Cell Leukemia: A Review.

Hairy cell leukemia (HCL) is a chronic B-cell leukemia noted for an indolent course that ultimately results in cytopenias and massive splenomegaly. Whereas treatment with the nucleoside purine analogues cladribine and pentostatin results in lengthy remissions in nearly all patients with HCL, most patients will experience relapse while a small percentage of patients' disease fails to respond to therapy in the first place. Retreatment with a purine nucleoside analogue often leads to an effective but limited response. For decades, few other viable therapeutic options were available to these patients who required retreatment. Recently, new insights into the mechanism of disease of HCL have led to research in new potential treatment agents, either alone or with a purine nucleoside analogue. Clinical trials with rituximab, bendamustine, and conjugate immunotoxins will reveal what role these therapies will have in HCL treatment. A better understanding of the BRAF/MEK/ERK pathway and the B-cell signaling pathway has allowed further exploration into the novel drugs vemurafenib, dabrafenib, trametinib, and ibrutinib.

Polyamines Impair Immunity to Helicobacter pylori by Inhibiting L-Arginine Uptake Required for Nitric Oxide Production.

BACKGROUND & AIMS: Helicobacter pylori-induced immune responses fail to eradicate the bacterium. Nitric oxide (NO) can kill H pylori. However, translation of inducible NO synthase (iNOS) and NO generation by H pylori-stimulated macrophages is inhibited by the polyamine spermine derived from ornithine decarboxylase (ODC), and is dependent on availability of the iNOS substrate L-arginine (L-Arg). We determined if spermine inhibits iNOS-mediated immunity by reducing L-Arg uptake into macrophages. METHODS: Levels of the inducible cationic amino acid transporter (CAT)2, ODC, and iNOS were measured in macrophages and H pylori gastritis tissues. L-Arg uptake, iNOS expression, and NO levels were assessed in cells with small interfering RNA knockdown of CAT2 or ODC, and in gastric macrophages. The ODC inhibitor, α-difluoromethylornithine, was administered to H pylori-infected mice for 4 months after inoculation. RESULTS: H pylori induced CAT2 and uptake of L-Arg in RAW 264.7 or primary macrophages. Addition of spermine or knockdown of CAT2 inhibited L-Arg uptake, NO production, and iNOS protein levels, whereas knockdown of ODC had the opposite effect. CAT2 and ODC were increased in mouse and human H pylori gastritis tissues and localized to macrophages. Gastric macrophages from H pylori-infected mice showed increased ODC expression, and attenuated iNOS and NO levels upon ex vivo H pylori stimulation versus cells from uninfected mice. α-Difluoromethylornithine treatment of infected mice restored L-Arg uptake, iNOS protein expression, and NO production in gastric macrophages, and significantly reduced both H pylori colonization levels and gastritis severity. CONCLUSIONS: Up-regulation of ODC in gastric macrophages impairs host defense against H pylori by suppressing iNOS-derived NO production.