Observational study of lenalidomide in patients with mantle cell lymphoma who relapsed/progressed after or were refractory/intolerant to ibrutinib (MCL-004).

BACKGROUND: The observational MCL-004 study evaluated outcomes in patients with relapsed/refractory mantle cell lymphoma who received lenalidomide-based therapy after ibrutinib failure or intolerance. METHODS: The primary endpoint was investigator-assessed overall response rate based on the 2007 International Working Group criteria. RESULTS: Of 58 enrolled patients (median age, 71 years; range, 50-89), 13 received lenalidomide monotherapy, 11 lenalidomide plus rituximab, and 34 lenalidomide plus other treatment. Most patients (88%) had received ≥ 3 prior therapies (median 4; range, 1-13). Median time from last dose of ibrutinib to the start of lenalidomide was 1.3 weeks (range, 0.1-21.7); 45% of patients had partial responses or better to prior ibrutinib. Primary reasons for ibrutinib discontinuation were lack of efficacy (88%) and ibrutinib toxicity (9%). After a median of two cycles (range, 0-11) of lenalidomide-based treatment, 17 patients responded (8 complete responses, 9 partial responses), for a 29% overall response rate (95% confidence interval, 18-43%) and a median duration of response of 20 weeks (95% confidence interval, 2.9 to not available). Overall response rate to lenalidomide-based therapy was similar for patients with relapsed/progressive disease after previous response to ibrutinib (i.e., ≥PR) versus ibrutinib-refractory (i.e., ≤SD) patients (30 versus 32%, respectively). The most common all-grade treatment-emergent adverse events after lenalidomide-containing therapy (n = 58) were fatigue (38%) and cough, dizziness, dyspnea, nausea, and peripheral edema (19% each). At data cutoff, 28 patients have died, primarily due to mantle cell lymphoma. CONCLUSION: Lenalidomide-based treatment showed clinical activity, with no unexpected toxicities, in patients with relapsed/refractory mantle cell lymphoma who previously failed ibrutinib therapy. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT02341781 . Date of registration: January 14, 2015

Molecular signatures for CCN1, p21 and p27 in progressive mantle cell lymphoma

Mantle cell lymphoma (MCL) is a comparatively rare non-Hodgkin’s lymphoma characterised by overexpression of cyclin D1.Many patients present with or progress to advanced stage disease within 3 years. MCL is considered an incurable disease withmedian survival between 3 and 4 years. We have investigated the role(s) of CCN1 (CYR61) and cell cycle regulators inprogressive MCL. We have used the human MCL cell lines REC1 G519 > JVM2 cells by RQ-PCR, depicting a decrease in CCN1expression with disease progression. Investigation of CCN1 isoform expression by western blotting showed that whilst expres-sion of full-length CCN1 was barely altered in the cell lines, expression of truncated forms (18–20 and 28–30 kDa) decreasedwith disease progression. We have then demonstrated that cyclin D1 and cyclin dependent kinase inhibitors (p21CIP1and p27KIP1)are also involved in disease progression. Cyclin D1 was highly expressed in REC1 cells (OD: 1.0), reduced to one fifth in G519cells (OD: 0.2) and not detected by western blotting in JVM2 cells. p27KIP1followed a similar profile of expression as cyclin D1.Conversely, p21CIP1was absent in the REC1 cells and showed increasing expression in G519 and JVM2 cells. Subcellularlocalization detected p21CIP1/p27KIP1primarily within the cytoplasm and absent from the nucleus, consistent with altered roles in treatment resistance. Dysregulation of the CCN1 truncated forms are associated with MCL progression. In conjunction withreduced expression of cyclin D1 and increased expression of p21, this molecular signature may depict aggressive disease andtreatment resistance

Key issues in the conservation of the Australian coastal archaeological record: natural and human impacts

Australia has an extensive coastline extending over 60,000 km through diverse tropical and temperate environments. Indigenous archaeological sites are found along this coastline from the time of earliest settlement at least 50,000 years ago. However, Pleistocene sites are rare owing largely to the destructive impacts of sea-level change associated with the end of the last ice age around 10,000 years ago. After this sites are more numerous but there is variability around the coastline due to the impact of a range of both natural and human factors. Here we focus on six key issues impacting on the development and conservation of coastal archaeological deposits: sea-levels, climate change, cyclones, storms, tsunamis and contemporary human impacts. A number of examples of these impacts are discussed from across Australia. Managing and monitoring of sites has been limited in Australia and geoindicators are discussed as a means of developing a long-term measurement of continuing impacts