Weekly treatment with irinotecan plus fluorouracil and leucovorin is superior to a widely used regimen of fluorouracil and leucovorin for metastatic colorectal cancer in terms of progression-free survival and overall survival.

BACKGROUND Patients with relapsed chronic lymphocytic leukemia (CLL) who have clinically significant coexisting medical conditions are less able to undergo standard chemo-therapy. Effective therapies with acceptable side-effect profiles are needed for this patient population. METHODS In this multicenter, randomized, double-blind, placebo-controlled, phase 3 study, we assessed the efficacy and safety of idelalisib, an oral inhibitor of the delta iso-form of phosphatidylinositol 3-kinase, in combination with rituximab versus rituximab plus placebo. We randomly assigned 220 patients with decreased renal function, previous therapy-induced myelosuppression, or major coexisting illnesses to receive rituximab and either idelalisib (at a dose of 150 mg) or placebo twice daily. The primary end point was progression-free survival. At the first prespecified interim analysis, the study was stopped early on the recommendation of the data and safety monitoring board owing to overwhelming efficacy. RESULTS The median progression-free survival was 5.5 months in the placebo group and was not reached in the idelalisib group (hazard ratio for progression or death in the idelalisib group, 0.15; P<0.001). Patients receiving idelalisib versus those receiving placebo had improved rates of overall response (81% vs. 13%; odds ratio, 29.92; P<0.001) and overall survival at 12 months (92% vs. 80%; hazard ratio for death, 0.28; P = 0.02). Serious adverse events occurred in 40% of the patients receiving idelalisib and rituximab and in 35% of those receiving placebo and rituximab. CONCLUSIONS The combination of idelalisib and rituximab, as compared with placebo and rituximab, significantly improved progression-free survival, response rate, and overall survival among patients with relapsed CLL who were less able to undergo chemo-therapy. (Funded by Gilead; ClinicalTrials.gov number, NCT01539512.)

Nonsense mutations promote premature translational termination and cause anywhere from 5-70% of the individual cases of most inherited diseases. Studies on nonsense-mediated cystic fibrosis have indicated that boosting specific protein synthesis from <1% to as little as 5% of normal levels may greatly reduce the severity or eliminate the principal manifestations of disease. To address the need for a drug capable of suppressing premature termination, we identified PTC124-a new chemical entity that selectively induces ribosomal readthrough of premature but not normal termination codons. PTC124 activity, optimized using nonsense-containing reporters, promoted dystrophin production in primary muscle cells from humans and mdx mice expressing dystrophin nonsense alleles, and rescued striated muscle function in mdx mice within 2-8 weeks of drug exposure. PTC124 was well tolerated in animals at plasma exposures substantially in excess of those required for nonsense suppression. The selectivity of PTC124 for premature termination codons, its well characterized activity profile, oral bioavailability and pharmacological properties indicate that this drug may have broad clinical potential for the treatment of a large group of genetic disorders with limited or no therapeutic options.

Background Phosphatidylinositol-3-kinase delta (PI3Kδ) mediates B-cell receptor signaling and microenvironmental support signals that promote the growth and survival of malignant B lymphocytes. In a phase 1 study, idelalisib, an orally active selective PI3Kδ inhibitor, showed antitumor activity in patients with previously treated indolent non-Hodgkin's lymphomas. Methods In this single-group, open-label, phase 2 study, 125 patients with indolent non-Hodgkin's lymphomas who had not had a response to rituximab and an alkylating agent or had had a relapse within 6 months after receipt of those therapies were administered idelalisib, 150 mg twice daily, until the disease progressed or the patient withdrew from the study. The primary end point was the overall rate of response; secondary end points included the duration of response, progression-free survival, and safety. Results The median age of the patients was 64 years (range, 33 to 87); patients had received a median of four prior therapies (range, 2 to 12). Subtypes of indolent non-Hodgkin's lymphoma included follicular lymphoma (72 patients), small lymphocytic lymphoma (28), marginal-zone lymphoma (15), and lymphoplasmacytic lymphoma with or without Waldenström's macroglobulinemia (10). The response rate was 57% (71 of 125 patients), with 6% meeting the criteria for a complete response. The median time to a response was 1.9 months, the median duration of response was 12.5 months, and the median progression-free survival was 11 months. Similar response rates were observed across all subtypes of indolent non-Hodgkin's lymphoma, though the numbers were small for some categories. The most common adverse events of grade 3 or higher were neutropenia (in 27% of the patients), elevations in aminotransferase levels (in 13%), diarrhea (in 13%), and pneumonia (in 7%). Conclusions In this single-group study, idelalisib showed antitumor activity with an acceptable safety profile in patients with indolent non-Hodgkin's lymphoma who had received extensive prior treatment. (Funded by Gilead Sciences and others; ClinicalTrials.gov number, NCT01282424.)

Key Points Idelalisib was evaluated in 54 patients with heavily pretreated chronic lymphocytic leukemia, and target inhibition was documented in vivo. Oral idelalisib therapy demonstrated a favorable safety profile and rapidly induced durable disease control in the majority of patients.

In lymphocytes, the phosphoinositide 3-kinase (PI3K) isoform p110␦ (PI3K␦) transmits signals from surface receptors, including the B-cell receptor (BCR). CAL-101, a selective inhibitor of PI3K␦, displays clinical activity in CLL, causing rapid lymph node shrinkage and a transient lymphocytosis. Inhibition of pro-survival pathways, the presumed mechanism of CAL-101, does not explain this characteristic pattern of activity. Therefore, we tested CAL-101 in assays that model CLLmicroenvironment interactions in vitro.We found that CAL-101 inhibits CLL cell chemotaxis toward CXCL12 and CXCL13 and migration beneath stromal cells (pseudoemperipolesis) . IntroductionChronic lymphocytic leukemia (CLL), the most common leukemia in Western countries, is characterized by the accumulation of CD5 ϩ /CD23 ϩ monoclonal B cells in the blood and tissue compartments (marrow and secondary lymphatic tissues). 1 CLL cells are resistant to cell death in vivo. However, they rapidly die from spontaneous apoptosis once removed from the patient unless they are cocultured with accessory stromal cells, such as marrow stromal cells (MSCs) 2 or monocyte-derived nurse-like cells (NLCs). 3 Cross-talk between CLL cells and these supporting cells in tissue microenvironments comprises a complex signaling network that may be critical for disease progression and drug resistance. Interference with this cross-talk may constitute a new therapeutic target. Several molecular pathways related to leukemia cell migration, B-cell receptor (BCR) signaling, and interactions between CLL cells and T cells have been identified over recent years (reviewed in Burger et al 4 ).The chemokines, CXCL12 and CXCL13, are constitutively secreted by MSCs and NLCs 5,6 and attract CLL cells via their respective cognate chemokine receptors, CXCR4, CXCR5, thereby regulating homing and retention of the leukemia cells in the tissue compartments. In addition, BCR signaling in the lymphatic tissue microenvironment promotes the clonal expansion of normal and malignant B cells. 1,7,8 CLL cells isolated from lymph nodes 8 or high-risk patients 9 display gene expression profiles that indicate BCR activation. In response to BCR activation and in NLC cocultures, CLL cells secrete the chemokines CCL3 and CCL4 (also called MIP-1␣ and ␤), 10 presumably for recruitment of accessory cells, such as regulatory T cells. 11,12 We proposed that the secretion of CCL3 and CCL4 by CLL cells correlates with the responsiveness of the BCR, based on higher secretion of CCL3/4 in ZAP-70 ϩ cases, 10 and a close correlation between CCL3 plasma levels and ZAP-70, IgHV mutational status, and prognosis. 13 Phosphoinositide 3Ј-kinases (PI3Ks) integrate and transmit signals from diverse surface molecules, such as the BCR, 14 chemokine receptors, and adhesion molecules, thereby regulating key cellular functions, including growth, survival, and migration. 15 The PI3Ks are divided into 3 classes; I, II, and III. The class I kinases contain 4 isoforms designated PI3K␣, ␤, ␥, and ␦. While the PI3K␣ and ␤ isoforms are ...

No abstract

Walking abnormalities are prominent in Duchenne muscular dystrophy (DMD). We modified the 6-minute walk test (6MWT) for use as an outcome measure in patients with DMD and evaluated its performance in 21 ambulatory boys with DMD and 34 healthy boys, ages 4 to 12 years. Boys with DMD were tested twice, approximately 1 week apart; controls were tested once. The groups had similar age, height, and weight. All tests were completed. Boys who fell recovered rapidly from falls without injury. Mean +/- SD [range] 6-minute walk distance (6MWD) was lower in boys with DMD than in controls (366 +/- 83 [125-481] m vs. 621 +/- 68 [479-754] m; P < 0.0001; unpaired t-test). Test-retest correlation for boys with DMD was high (r = 0.91). Stride length (R(2) = 0.89; P < 0.0001) was the major determinant of 6MWD for both boys with DMD and controls. A modified 6MWT is feasible and safe, documents disease-related limitations on ambulation, is reproducible, and offers a new outcome measure for DMD natural history and therapeutic trials.