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Purpose: Waldenstrom's macroglobulinemia (WM) is a B-cell disorder. Despite advances in the therapy, WM remains incurable. As such, novel therapeutic agents are needed for the treatment of WM. Experimental Design: In this multicenter study, 27 patients with WM received up to eight cycles of bortezomib at 1.3 mg/m 2 on days 1, 4, 8, and 11. All but one patient had relapsed/or refractory disease. Results: Following therapy, median serum IgM levels declined from 4,660 to 2,092 mg/dL (P <0.0001).The overall response rate was 85%, with10 and13 patients achieving minor and major responses, respectively. Responses were prompt and occurred at median of1.4 months.The median time to progression for all responding patients was 7.9 (range, 3-21.4+) months.The most common grade III/IV toxicities occurring in z5% of patients were sensory neuropathies (22.2%), leukopenia (18.5%), neutropenia (14.8%), dizziness (11.1%), and thrombocytopenia (7.4%). Sensory neuropathies resolved or improved in nearly all patients following cessation of therapy. Conclusions:The results of these studies show that bortezomib is an active agent in relapsed and refractory WM.

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Thalidomide enhances rituximab-mediated, antibody-dependent, cell-mediated cytotoxicity. We therefore conducted a phase 2 study using thalidomide and rituximab in symptomatic Walden-strom macroglobulinemia (WM) patients naive to either agent. Intended therapy consisted of daily thalidomide (200 mg for 2 weeks, then 400 mg for 50 weeks) and rituximab (375 mg/m 2 per week) dosed on weeks 2 to 5 and 13 to 16. Twenty-five patients were enrolled, 20 of whom were untreated. Responses were complete response (n 1), partial response (n 15), and major response (n 2), for overall and major response rate of 72% and 64%, respectively, on an intent-to-treat basis. Median serum IgM decreased from 3670 to 1590 mg/dL (P < .001), whereas median hematocrit rose from 33.0% to 37.6% (P .004) at best response. Median time to progression for responders was 38 months. Peripheral neuropathy to thalidomide was the most common adverse event. Among 11 patients experiencing grade 2 or greater neuropathy, 10 resolved to grade 1 or less at a median of 6.7 months. Thalido-mide in combination with rituximab is active and produces long-term responses in WM. Lower doses of thalidomide (ie, < 200 mg/day) should be considered given the high frequency of treatment-related neuropathy in this patient population. This trial is registered at www. clinicaltrials.gov as #NCT00142116. (Blood. 2008;112:4452-4457) Introduction Monoclonal antibodies have been successfully used to treat patients with B-cell malignancies, including Waldenstrom macroglobu-linemia (WM). Most of these efforts have focused on the use of rituximab, a chimeric human IgG 1 monoclonal antibody, which targets CD20, which is widely expressed in WM. 1,2 Studies using standard-dose rituximab therapy have demonstrated activity in WM, with overall response rates of 27% to 35% and median durations of response from 8 to 27 months. 2-7 More recently, the use of extended schedule rituximab has been evaluated wherein patients received 8 infusions of rituximab (375 mg/m 2 per week) at weeks 1 to 4 and 12 to 16. Overall response rates of 44% to 48% were observed in these studies, with median durations of response from 16 to 29 months. 8,9 Among WM patients receiving rituximab as monotherapy, lower response rates have been observed in those patients with high serum IgM (6000 mg/dL) and beta-2 microglobulin (B 2 M; 3.0 mg/L) levels, as well as homozygous expression of phenylalanine at amino acid position 158 on CD16 (FcRIIIA-158). 8-10 Studies combining rituximab with chemotherapy have also been explored in WM. 11 The combination of nucleoside analogs plus rituximab has yielded major response rates of 70% to 90%, 12-15 whereas the combinations of CHOP-R (cyclophosphamide, adria-mycin, vincristine, prednisone, rituximab) or DC-R (dexametha-sone, cyclophosphamide, rituximab) have resulted in response rates of 80% to 90%. 16-18 Median time to progression (TTP) in excess of 3 years has been reported with these combinations. Although these combinations have produced more impressive responses, greater toxi...

SUMMARY. , an inhibitor of the hepatitis C virus (HCV) nonstructural protein (NS) 3/4A, demonstrates potent activity against HCV genotypes 1-6 and improved coverage against commonly encountered NS3 resistanceassociated variants (RAVs). In this study, the safety, tolerability, antiviral activity and pharmacokinetics (PK) of GS-9857 were evaluated in patients with chronic HCV genotype 1-4 infection. Patients with genotype 1-4 infection received placebo or once-daily GS-9857 at doses ranging from 50 to 300 mg for 3 days under fasting conditions. GS-9857 was well tolerated; all reported adverse events (AEs) were mild or moderate in severity. Diarrhoea and headache were the most commonly reported AEs. Grade 3 or 4 laboratory abnormalities were observed in 17% of patients receiving GS-9857; there were no Grade 3 or 4 abnormalities in alanine aminotransferase, aspartate aminotransferase or alkaline phosphatase levels. GS-9857 demonstrated potent antiviral activity in patients with chronic HCV infection, achieving mean and median maximum reductions in HCV RNA of ≥3 log 10 IU/mL following administration of a 100-mg dose in patients with HCV genotype 1a, 1b, 2, 3 or 4 infection. The antiviral activity of GS-9857 was unaffected by the presence of pretreatment NS3 RAVs. In patients with genotype 1-4 infection, GS-9857 exhibited linear PK and was associated with a median half-life of 29-42 h, supporting once-daily dosing. Thus, the tolerability, efficacy and pharmacokinetic profile of GS-9857 support its further evaluation for treatment of patients with chronic HCV infection.Keywords: GS-9857, hepatitis C virus, NS3/4A protease inhibitor.Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; AUC 0-24 , area under the plasma concentration vs time curve up to 24 h; AUC inf , area under the plasma concentration vs time curve extrapolated to infinity; AUC last , area under the plasma concentration vs time curve from zero to the last quantifiable concentration; BMI, body mass index; C 24 , observed plasma concentration at 24 h postdose; C last , last observed quantifiable plasma drug concentration; CL/F, apparent oral clearance of drug following administration; C max , maximum plasma concentration; DAA, direct-acting antiviral; ECG, electrocardiogram; EC 50 , dose or systemic exposure required to produce 50% of the maximal drug induced anti-HCV activity; E max , maximal anti-HCV activity; HCV, hepatitis C virus; LC/MS/MS, liquid chromatography tandem mass spectroscopy; LLOQ, lower limit of quantification; MedDRA, Medical Dictionary for Regulatory Activities; NS, nonstructural protein; PK, pharmacokinetics; PD, pharmacodynamics; RAV, resistance-associated variant; RNA, ribonucleic acid; t 1/2 , elimination half-life; T last , time of last observed quantifiable plasma drug concentration; T max , time of maximum plasma concentration; ULN, upper limit of normal; k z , terminal elimination rate constant.Correspondence: Eric Lawitz, MD, The