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Both continuous therapy with acalabrutinib and fixed-duration therapy with venetoclax–obinutuzumab are effective for previously untreated chronic lymphocytic leukaemia. We hypothesised that frontline time-limited, minimal residual disease (MRD)-guided triplet therapy with acalabrutinib, venetoclax, and obinutuzumab would induce deep (ie, more patients with undetectable MRD) and durable remissions. In this open-label, single-arm, investigator-sponsored, phase 2 study, patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma were recruited from two academic hospitals in Boston, MA, USA. Eligible patients were aged 18 years or older, with an Eastern Cooperative Oncology Group performance status of 0–2, and were treatment naive. Patients were treated in 28 day cycles. Acalabrutinib monotherapy was given orally at 100 mg twice daily for cycle 1, then combined for six cycles with intravenous obinutuzumab (100 mg on cycle 2 day 1, 900 mg on day 2, 1000 mg on day 8, and 1000 mg on day 15 and on day 1 of cycles 3–7); and from the beginning of cycle 4, oral venetoclax was dosed daily using an accelerated ramp-up from 20 mg on day 1 to 400 mg by day 22 and continued at this dose thereafter. Patients continued on acalabrutinib 100 mg twice daily and venetoclax 400 mg once daily until day 1 of cycle 16 or day 1 of cycle 25. If the patient had undetectable MRD in the bone marrow they were given the option to discontinue therapy at the start of cycle 16 (if also in complete remission) or at the start of cycle 25 (if at least in partial remission). The primary endpoint was complete remission with undetectable MRD in the bone marrow (defined as <1 chronic lymphocytic leukaemia cell per 10 000 leucocytes as measured by four-colour flow cytometry), at cycle 16 day 1. Safety and activity endpoints were assessed in all patients who received at least one dose of any study drug. This study is registered with ClinicalTrials.gov, NCT03580928, and is ongoing. Between Aug 2, 2018, and May 23, 2019, 37 patients with chronic lymphocytic leukaemia were enrolled and all received at least one dose of any study drug. The median age of patients was 63 years (IQR 57–70), and ten (27%) were female and 27 (73%) were male. Median follow-up was 27·6 months (IQR 25·1–28·2). At cycle 16 day 1, 14 (38% [95% CI 22–55]) of 37 participants had a complete remission with undetectable MRD in the bone marrow. The most common grade 3 or 4 haematological adverse event was neutropenia (16 [43%] of 37 patients). The most common grade 3–4 non-haematological adverse events were hyperglycaemia (three [8%]) and hypophosphataemia (three [8%]). Serious adverse events occurred in nine (24%) patients; the most common was neutropenia in three (8%) patients. There have been no deaths on study. Acalabrutinib, venetoclax, and obinutuzumab is a highly active and well tolerated frontline therapy for chronic lymphocytic leukaemia. Although the primary endpoint of this study was not met, the high proportion of patients who had undetectable MRD in the bone marrow supports further investigation of this regimen, which is being tested against acalabrutinib–venetoclax and chemoimmunotherapy in an ongoing phase 3 study (NCT03836261). AstraZeneca and a Dana-Farber Cancer Institute Collaborative Award.

In recent years, a revolution in the management of chronic lymphocytic leukemia (CLL) has centered on the targeting of the B cell receptor (BCR) signaling pathway. Our improved understanding of the biology of cell signaling in CLL and the development of oral kinase inhibitors directed at the BCR pathway has led to the approval of two new agents and has the potential to radically change the treatment of CLL in both the relapsed/refractory and upfront settings. In this review, we will describe the underlying biology of the BCR signaling pathway. We will discuss the landmark clinical trials resulting in the approval of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib and the PI3Kδ inhibitor idelalisib. We will highlight ongoing trials that are evaluating the use of combinations of these agents with standard chemotherapy. We will evaluate some of the emerging data regarding toxicity, potential off-target effects, and mechanisms of resistance to BCR signaling pathway blockade. Finally, we will highlight some of the next-generation BCR pathway inhibitors currently in development.

The majority of patients with chronic lymphocytic leukemia (CLL) respond to chemo-immunotherapy. However, long-term remission remains elusive and the majority of patients will die of complications related to CLL. In this review we discuss the recent developments in targeted therapy for CLL. Targeted therapy has evolved beyond the cell surface targeting of CD20 with rituximab. Our review focuses on the evolution of antibody therapy in CLL, strategies to target effector T cells to the tumor, inhibition of the B-cell receptor signaling pathway, and finally targeting the mediators of apoptosis. With our improved understanding of the biology of CLL, the evolution of targeted therapy has resulted in significant clinical responses in patients who are refractory to traditional treatment options and holds the potential for a future where we can manage this disease without chemotherapy.

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia. The current treatment paradigm involves the use of chemoimmunotherapy, when patients develop an indication for therapy. With this strategy, a majority of patients will obtain a remission, though cure remains elusive. While treatable, the majority of CLL patients will die of complications of their disease. Recent advances in the understanding of the importance of the B cell receptor (BCR) pathway in CLL have led to the development of a number of agents targeting this pathway. In this review, we discuss recent developments in the targeting of the BCR pathway, with a focus on CC-292. CC-292 covalently binds to Bruton's tyrosine kinase, a key mediator of BCR signaling, and has demonstrated preclinical and clinical activity in CLL, with acceptable tolerability. Based on the success of CC-292 and other inhibitors of the BCR pathway, these agents are being investigated in combination with standard therapy, with the hope that they will increase the depth and length of response, without significant toxicity.

Chronic lymphocytic leukemia (CLL), the most common leukemia in adults, is standardly managed with chemotherapy in combination with the anti-CD20 antibody rituximab. In this review, we discuss the history, use, and evolution of rituximab in the treatment of CLL and explore the next generation CD20 antibodies ofatumumab and obinutuzumab with a focus on recent clinical trials. Increased understanding of the importance of B cell receptor (BCR) signaling in CLL has resulted in the development of several drugs with significant clinical activity that are ideally suited for combination with CD20 therapy as is being currently explored. Moving forward, these developments have the potential to result in treatment regimens that do not include traditional chemotherapeutic agents, which is of particular importance in CLL given the late onset of diagnosis and potential frailty of the patients. Keywords: CLL, monoclonal antibody, rituximab, ofatumumab, obinutuzumab

Gilg. is a neotropical vine native to Central America, investigated as part of a targeted study of the plant family Marcgraviaceae. Our previous research showed that extract of leaf and small branch extract had anxiolytic effects in animals and acts as an agonist for the GABA receptor at the benzodiazepine binding site. To date, the potential effects of and its constituents on reconsolidation have not been assessed. Reconsolidation, the process by which formed memories are rendered labile and susceptible to change, may offer a window of opportunity for pharmacological manipulation of learned fear. Here, we assessed the effects of crude extract and isolated phytochemicals (orally administered) on the reconsolidation of conditioned fear. In addition, we explored whether betulin (BE), a closely related molecule to betulinic acid (BA, an active principal component of ), has effects on reconsolidation of learned fear and whether BE may synergize with BA to enhance attenuation of learned fear. Male Sprague-Dawley rats received six 1.0-mA continuous foot shocks (contextual training). Twenty-four hours later, rats were re-exposed to the context (but in the absence of foot shocks). Immediately following memory retrieval (recall), rats received oral administration of extract at various doses (8-75 mg/kg) or diazepam (1 mg/kg). In separate experiments, we compared the effects of BA (2 mg/kg), BE (2 mg/kg), and BA + BE (2 mg/kg BA + 2 mg/kg BE). The freezing response was assessed either 24 h later (day 3) or 5 days later (day 7). Effects of phytochemicals on fear expression were also explored using the elevated plus maze paradigm. leaf extract significantly attenuated the reconsolidation of contextual fear at the 25- and 75-mg/kg doses, but not at the 8-mg/kg dose. Furthermore, BA + BE, but not BA or BE alone, attenuated the reconsolidation of learned fear and exerted an anxiolytic-like effect on fear expression.