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.)

Background Irreversible inhibition of Bruton tyrosine kinase (Btk) by ibrutinib represents a significant therapeutic advance for chronic lymphocytic leukemia (CLL). However, ibrutinib also irreversibly inhibits alternative kinase targets, which potentially compromise its therapeutic index. Acalabrutinib (ACP-196) is a more selective irreversible Btk inhibitor specifically designed to improve upon the safety and efficacy of first generation Btk inhibitors. Methods Sixty-one patients with relapsed CLL were treated in a phase 1–2 multicenter study designed to assess the safety, efficacy, pharmacokinetics and pharmacodynamics of oral acalabrutinib. Patients were continuously treated with acalabrutinib 100 to 400 mg once daily in the dose-escalation portion of the study, and 100 mg twice daily in the expansion portion. Results Patient demographics include a median age of 62 years; median of 3 prior therapies; 31% del(17)(p13.1) and 75% unmutated immunoglobulin heavy chain variable genes. No dose-limiting toxicities occurred. The most common adverse events observed were headache (43%), diarrhea (39%) and increased weight (26%). Most adverse events were Grade 1–2. At a median follow-up of 14.3 months, the best overall response rate was 95%, including 85% partial response, 10% partial response with lymphocytosis and 5% stable disease. In patients with del(17)(p13.1), the best overall response was 100%. No cases of Richter’s transformation and only 1 CLL progression have occurred. Conclusions Acalabrutinib is a highly selective Btk inhibitor that provides effective and well tolerated treatment for patients with relapsed CLL, including those with del(17)(p13.1).

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.

Methyl- and hydroxyl-terminated phosphonic acid self-assembled monolayers (SAMs) were coated on Ti from aqueous solution. Dodecyl phosphate and dodecyltrichlorosilane SAMs were also coated on Ti using solution-phase deposition. The stability of SAMs on Ti was investigated in Tris-buffered saline (TBS) at 37 degrees C using X-ray photoelectron spectroscopy, contact angle goniometry, and atomic force microscopy. For comparison purposes, a hydroxyl-terminated thiol SAM was coated on Au, and its stability was also investigated under similar conditions. In TBS, a significant proportion of phosphonic acid or phosphate molecules were desorbed from the Ti surface within 1 day, while the trichlorosilane SAM on Ti or thiol SAM on Au was stable for up to 7 days under similar conditions. The stability of hydroxyl-terminated phosphonic acid SAM coated Ti and thiol SAM coated Au was investigated in ambient air and ultraviolet (UV) light. In ambient air, the phosphonic acid SAM on Ti was stable for up to 14 days, while the thiol SAM on Au was not stable for 1 day. Under UV-radiation exposure, the alkyl chains of the phosphonic acid SAM were decomposed, leaving only the phosphonate groups on the Ti surface after 12 h. Under similar conditions, decomposition of alkyl chains of the thiol SAM was observed on the Au surface accompanied by oxidation of thiolates.

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GS-1101 (CAL-101 IntroductionHodgkin lymphoma (HL) is a malignant lymphoma of B-cell origin. 1 The malignant cells, known as Reed-Sternberg (RS) cells, represent less than 2% of the tumor mass, the remainder composed of a mix of reactive inflammatory cells attracted by the RS cells. Patients usually present with lymphadenopathy, organomegaly, and constitutional symptoms. 2 Chemotherapy with or without radiation cures most patients. However, some patients develop recurrent disease and are given sequential chemotherapeutic or immunotherapeutic agents to control tumor growth. 3 Unfortunately, cumulative toxicities and progressive resistance limit benefits. Safer therapies with novel mechanisms of action are needed for patients with relapsed HL.Phosphatidylinositol 3-kinases (PI3Ks) are enzymes that mediate signals from cell surface receptors. The 4 class I PI3K isozymes (PI3K␣, PI3K␤, PI3K␥, and PI3K␦) regulate a variety of cellular functions through the production of phosphatidylinositol-3,4,5-triphosphate. 4 Generation of phosphatidylinositol-3,4,5-triphosphate activates the downstream serine/threonine kinase, Akt, and the mammalian target of rapamycin (mTOR), both of which have positive effects on cell survival, proliferation, growth, and metabolism. 5,6 Dysregulation of the PI3K/Akt/mTOR pathway is important in the etiology of human malignancies. 5,7 Of the several PI3K isoforms, PI3K␦ has been shown to play a pivotal role in B-cell signaling in response to chemokines and cytokines. [8][9][10] Past studies have indicated a role for the PI3K/Akt/mTOR pathway in the pathogenesis of HL 11,12 and have suggested that PI3K might constitute an important therapeutic target in this disease. GS-1101 is a novel, oral, PI3K␦-specific inhibitor that has shown activity in other types of B-cell cancers. 8,9,13,14 We now characterize the activity of GS-1101 in cellular models of HL, providing translational support for PI3K␦ inhibition as a novel strategy for the treatment of HL. Methods Immunoblotting and ELISA analysisWhole-cell lysates were analyzed on 10% polyacrylamide gels, transferred to polyvinylidene difluoride (PVDF), blocked, probed with antibodies, and detected using the Odessy from LiCor as previously described. 15 The effect of GS-1101 on CCL5 secretion was measured as previously described. 8 After 24 hours, supernatants were harvested and assayed for CCL5 by quantitative ELISA according to the manufacturer's instructions (Quantikine, R&D Systems). Cell viability and apoptosisCell viability was assessed using Cell Titer Aqueous One Solution Cell Proliferation Assay reagent (Promega) following the manufacturer's protocol. For cell-cycle analysis, cells were permeabilized, stained with propidium iodide, and subjected to FACS evaluation of labeled DNA. Apoptosis was measured by annexin V-FITC/7-amino-actinomycin D (7-AAD) labeling followed by fluorescence flow cytometry as previously described. 9 ImmunohistochemistryImmunohistochemical methods to detect expression of the four PI3K isoforms were performed using routin...

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