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 ...

• In 64 older patients with untreated CLL or small lymphocytic leukemia, treatment with idelalisib plus rituximab was generally well tolerated.• The combination produced a very high response rate (97%), including 19% complete remission.Idelalisib is a first-in-class oral inhibitor of PI3Kd that has shown substantial activity in patients with relapsed/refractory chronic lymphocytic leukemia (CLL Progression-free survival was 83% at 36 months. The most frequent (>30%) adverse events (any grade) were diarrhea (including colitis) (64%), rash (58%), pyrexia (42%), nausea (38%), chills (36%), cough (33%), and fatigue (31%). Elevated alanine transaminase/aspartate transaminase was seen in 67% of patients (23% grade ‡3). The combination of idelalisib and rituximab was highly active, resulting in durable disease control in treatment-naïve older patients with CLL. These results support the further development of idelalisib as initial treatment of CLL. This study is registered at ClinicalTrials.gov as #NCT01203930. (Blood. 2015;126(25):2686-2694

Key Points This clinical study assessed idelalisib, a selective PI3Kδ inhibitor, in 64 patients with relapsed, indolent non-Hodgkin lymphoma. Idelalisib treatment rapidly induced durable disease responses in heavily pretreated patients with a favorable safety profile.

• This clinical study assessed idelalisib, a selective PI3Kd inhibitor, in 40 patients with relapsed/refractory MCL.• In a dose-escalation trial in heavily pretreated patients, an overall response rate of 40% was observed with an acceptable safety profile.Idelalisib, an oral inhibitor of phosphatidylinositol-3-kinase d (PI3Kd), was evaluated in a 48-week phase 1 study (50-350 mg daily or twice daily) enrolling 40 patients with relapsed or refractory mantle cell lymphoma (MCL). Primary outcome was safety and dose-limiting toxicity (DLT). Secondary outcomes were pharmacokinetic parameters, pharmacodynamic effects, overall response rate (ORR), progression-free survival (PFS), and duration of response (DOR). Patients without DLT and no evidence of disease progression after 48 weeks enrolled in the extension study. Patients had median age of 69 years (range, 52-83) and received median of 4 prior therapies (1-14); 17 of 40 patients (43%) were refractory to their most recent treatment. Median duration of idelalisib treatment was 3.5 months (range, 0.7-30.7), with 6 (15%) continuing extension treatment. Common grade ‡3 adverse events (AEs) included (total%/grade ‡3%) diarrhea (40/18), nausea (33/5), pyrexia (28/0), fatigue (25/3), rash (23/3), decreased appetite (20/15), upper respiratory infection (20/0), pneumonia (13/10), and alanine transaminase or aspartate transaminase elevations (60/20). ORR was 16 of 40 patients (40%), with CR in 2 of 40 patients (5%). Median DOR was 2.7 months, median PFS was 3.7 months, and 1-year PFS was 22%. These data provide proof of concept that targeting PI3Kd is a viable strategy and worthy of additional study in MCL. This trial was registered at www.clinicaltrials.gov as #NCT00710528. (Blood. 2014;123(22):3398-3405)

The transient receptor potential (TRP) superfamily consists of a large number of nonselective cation channels with variable degree of Ca(2+)-permeability. The 28 mammalian TRP channel proteins can be grouped into six subfamilies: canonical, vanilloid, melastatin, ankyrin, polycystic, and mucolipin TRPs. The majority of these TRP channels are expressed in different cell types including both excitable and nonexcitable cells of the cardiovascular system. Unlike voltage-gated ion channels, TRP channels do not have a typical voltage sensor, but instead can sense a variety of other stimuli including pressure, shear stress, mechanical stretch, oxidative stress, lipid environment alterations, hypertrophic signals, and inflammation products. By integrating multiple stimuli and transducing their activity to downstream cellular signal pathways via Ca(2+) entry and/or membrane depolarization, TRP channels play an essential role in regulating fundamental cell functions such as contraction, relaxation, proliferation, differentiation, and cell death. With the use of targeted deletion and transgenic mouse models, recent studies have revealed that TRP channels are involved in numerous cellular functions and play an important role in the pathophysiology of many diseases in the cardiovascular system. Moreover, several TRP channels are involved in inherited diseases of the cardiovascular system. This review presents an overview of current knowledge concerning the physiological functions of TRP channels in the cardiovascular system and their contributions to cardiovascular diseases. Ultimately, TRP channels may become potential therapeutic targets for cardiovascular diseases.

The efficacy and safety of tadalafil, dosed once a day for the treatment of erectile dysfunction, was assessed in a randomized, double-blind, placebo-controlled, parallel-design study at 15 US centers. Following a 4-week treatment-free run-in period, patients (X18 years of age) were randomly assigned to 24 weeks treatment with tadalafil 2.5 mg, tadalafil 5 mg or placebo. Primary efficacy endpoints were change at 24 weeks in International Index of Erectile Function Erectile Function (EF) Domain score and mean per-patient percentage 'yes' responses to Sexual Encounter Profile diary questions 2 and 3. Tadalafil significantly improved erectile function compared with placebo for all three co-primary efficacy endpoints. Few patients discontinued because of adverse events (2.1%, placebo; 6.3%, tadalafil 2.5 mg; 4.1%, tadalafil 5 mg). Common treatment-emergent adverse events (X5%) were nasopharyngitis, influenza, viral gastroenteritis and back pain. Tadalafil 2.5 mg and 5 mg, dosed once a day for 24 weeks, was well tolerated and significantly improved erectile function.

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