Zanubrutinib (BGB-3111) is a next-generation Bruton tyrosine kinase inhibitor designed to be more selective with fewer off-target effects. We conducted a phase 1 study to assess the safety of its combination with obinutuzumab and evaluate early efficacy in 81 patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) or relapsed/refractory (R/R) follicular lymphoma (FL). In this phase 1b study, zanubrutinib was tolerable at 160 mg twice daily or 320 mg once daily combined with IV obinutuzumab in patients with CLL/SLL (n = 45) and FL (n = 36). Common adverse events (AEs) included upper respiratory tract infection (51%; n = 23), neutropenia (44%; n = 20), contusion (33%; n = 15), cough, diarrhea, or fatigue (27%; n = 12 each), and pyrexia (22%; n = 10) in CLL/SLL patients and upper respiratory tract infection (39%; n = 14), contusion (28%; n = 10), fatigue (25%; n = 9), and cough (22%; n = 8) in FL patients. Neutropenia was the most common grade 3/4 AE (CLL/SLL, 31% [n = 14]; FL, 14% [n = 5]). Five patients required temporary dose reductions, and 5 discontinued the study drug because of AEs. Overall response rate (ORR) was 100% (n = 20) in treatment-naïve CLL patients and 92% (n = 23) in R/R CLL patients. ORR in 36 R/R FL patients was 72% (n = 26), with 14 complete and 12 partial responses. Median follow-up was 29 months (range, 8-37) for CLL patients and 20 months (range, 2-37) for FL patients. Zanubrutinib and obinutuzumab combination therapy was generally well tolerated. This trial was registered at www.clinicaltrials.gov as #NCT02569476.

Constrictive pericarditis (CP) after allogeneic SCT may develop after infective pericarditis or pericardial GVHD. Primary effusion lymphoma (PEL), also a rare disease, is usually seen in immunocompromised patients and has a poor prognosis.We describe a case of CP and PEL developing in a patient after allo-SCT for CML. We believe it is the first documented case of these complications in this setting, and include rare FDG-PET images of PEL.A 42-year-old Italian-born man underwent a sibling allograft in 1987 for CML in chronic phase. Myeloablative conditioning was given with CY (60 mg/kg on days À6 and À5) and TBI (2 cGy twice daily on days À4, À3 and À2); complete donor engraftment ensued, with complete cytogenetic remission. Moderately severe chronic GVHD involving skin, oral mucosa, eyes and liver was treated with CYA, prednisolone and PUVA treatment before thalidomide was commenced, with good effect.Twenty-four months post allograft there were no other manifestations of GVHD, but he developed symptoms of pericarditis including chest pain, fever, tachycardia, hypotension and raised inflammatory markers. The electrocardiogram showed widespread ST elevation without elevation of creatine kinase MB, and chest X-ray showed a large pericardial effusion. No infective or autoimmune cause was identified and he improved with symptomatic management. Thalidomide was ceased, with no obvious immediate recurrence of GVHD.At subsequent follow --up the patient was hypotensive and complained of lethargy, dizziness and general malaise. After 6 months he developed right upper quadrant pain and abnormal liver function tests (LFTs), with alkaline phosphatase (ALP) 250 U/L (20 --175 U/L), gamma-glutamyl transferase (GGT) 550 U/L (o45 U/L) and normal transaminases and bilirubin. Ultrasound showed no cholelithiasis; liver biopsy demonstrated micronodular cirrhosis with no other specific features. Some months later, he developed ascites and peripheral oedema, managed with diuretic therapy. Symptoms and signs of chronic liver disease persisted for the next 20 years and were attributed to chronic hepatic GVHD. Cortisone acetate 37.5 mg daily caused marked improvement in appetite, energy and well being (although no improvement in LFTs), and was therefore continued despite normal adrenocorticotropic hormone levels.In 2010, 23 years post transplant, the patient deteriorated rapidly over 3 months. He was admitted to hospital with extreme lethargy, nausea, 10-kg weight loss and worsening ascites, peripheral oedema and hypotension, which did not respond to medical management.On examination he was hypotensive (systolic blood pressure 85 mm Hg), with a sinus tachycardia (100 b.p.m.) and elevated jugular venous pressure (9 cm). He had small pleural effusions, marked ascites and peripheral oedema to the groin. He was afebrile without palpable lymphadenopathy or hepatosplenomegaly.He had mild renal impairment, with creatinine level of 167 mmol/L (30 --120 mmol/L) and normal electrolytes.

Diffuse large B‐cell lymphoma (DLBCL) is the most common lymphoma subtype, accounting for 30–40% of lymphoma diagnoses. Although aggressive, cure is achievable in approximately 60% of cases with primary chemoimmunotherapy, and in a further substantial minority by salvage therapy and autologous stem cell transplantation. Despite promising activity in early phase clinical trials, no intensified or novel treatment regimen has improved outcomes over R‐CHOP21 in randomised studies. However, there remain several areas of controversy including the most appropriate prognostic markers, central nervous system prophylaxis and the optimal treatment for patients with high‐risk disease. This position statement presents an evidence‐based synthesis of the literature for application in Australasian practice.

There is a significantly increased risk of pregnancy complications in women with anti-phospholipid syndrome (APS). The risk is further heightened in those with previous arterial or venous thromboembolism and so-called 'triple positivity' for anti-phospholipid antibodies (i.e., when lupus anticoagulant, and anti-cardiolipin (aCL) and anti-β2 glycoprotein-I (anti-β2Gp-I) antibodies are all detected). Management of these cases is extremely difficult and little is available in the medical literature to guide therapy. This report describes the use of regular plasma exchanges (PEx) to bring about a successful pregnancy outcome in a woman with secondary APS and previous recurrent miscarriages. The patient was also anticoagulated with enoxaparin and administered aspirin, prednisolone, azathioprine and hydroxychloroquine. Through regular PEx and immunomodulation therapy, levels of aCL and anti-β2Gp-I antibodies were monitored and documented to fall as pregnancy progressed. Although the outcome in this case was successful, further experience is required before this regimen can be accepted as the standard of care for these patients at very high risk of pregnancy loss.

The treatment of chronic pain could benefit from additional non-opioid interventions. Virtual reality (VR) has been shown to be effective in decreasing pain for procedural or acute pain but to date there have been few studies on its use in chronic pain. The present study was an investigation of the impact of a virtual reality application for chronic pain. Thirty (30) participants with various chronic pain conditions were offered a five-minute session using a virtual reality application called Cool! Participants were asked about their pain using a 0-10 visual analog scale rating before the VR session, during the session and immediately after the session. They were also asked about immersion into the VR world and about possible side effects. Pain was reduced from pre-session to post-session by 33%. Pain was reduced from pre-session during the VR session by 60%. These changes were both statistically significant at the p < .001 level. Three participants (10%) reported no change between pre and post pain ratings. Ten participants (33%) reported complete pain relief while doing the virtual reality session. All participants (100%) reported a decrease in pain to some degree between pre-session pain and during-session pain. The virtual reality experience was found here to provide a significant amount of pain relief. A head mounted display (HMD) was used with all subjects and no discomfort was experienced. Only one participant noted any side effects. VR seems to have promise as a non-opioid treatment for chronic pain and further investigation is warranted.

14 pts (14/30, 46%) and 18 SAE's occurred in 12 pts (12/30, 40%).Four immune-related adverse events (IRAE) occurred: grade 3 rash, grade 1 hyperthyroidism, grade 2 colitis, and grade 3 pneumonitis (in a 78 y.o. with a history of tobacco use and COPD). One pt. died during cycle 1 from bleed of gastric DLBCL, despite inpatient management, and was not assessed for response or dose intensity.Anthracycline relative dose intensity was 94.7%. 26/29 received all planned P. ORR in 29 assessable pts was 93%: 24 CR (83%), 3 PR (19%) and 2 SD/PD (7%). 19 pts had PET-CR on EOT assessment; 3 had initial PR but a negative biopsy, and 2 had PR converted to CR with repeat PET. Among 8 pts with residual FDG-avid lesions on EOT PET, only 1 relapse occurred.At 16 months follow-up, four relapses and 2 deaths occurred, with PFS/OS of 82/97% at 18 months ( Figure 1). In 22 tested pts to date, 55% had PDL-1 tumor cell ≥ 30%, and PDL H-score (a weighted average) was 0 in 3 pts, 1-99 in 9 pts, and 100 or more in 10 pts. PFS was inferior in PDL1 H score 0 pts (p<.001) and IPI 3-5 pts (p=.07), but no different in GCB vs non-GCB. Conclusions: P + RCHOP did not show toxicity beyond what isexpected with RCHOP, and was associated with a high CR rate in this trial. FDG avid lesions in pts with PR were commonly false positives.Significant PDL-1 tumor staining was seen in most pts tested, and appears to predict PFS; final PDL-1 results will be presented. Our data supports further comparative study of P+RCHOP in DLBCL. Introduction: Bruton Tyrosine Kinase (BTK) plays a critical role in B cell receptor (BCR) signaling. Zanubrutinib is a selective and irreversible BTK inhibitor that has demonstrated potent inhibition of BTK preclinically, with minimal inhibition of other kinases; it has minimal effect on interleukin-2 inducible tyrosine kinase (ITK) and does not inhibit ITK-mediated rituximab-induced antibody-mediated cytotoxicity. Methods: This is a phase 1b study of the combination of zanubrutinib with obinutuzumab in patients with B-cell malignancies. Eligible ABSTRACT 121 patients had ECOG status of 0-2, neutrophil count >1000/μL, platelets >40,000/μL, adequate renal and hepatic function and no significant cardiac disease. Growth factors, transfusion and anticoagulation were allowed. The primary efficacy endpoint was objective response using 2007 International Working Group criteria. Results: As of 16Nov2018, enrollment was complete with 45 CLL/SLL patients (20 treatment-naïve [TN] and 25 R/R) and 36 R/R FL patients. Median follow-up was 25.5 mo (range: 7.9-33.5) for CLL/SLL and 17.8 mo (range: 2.3-33.8) for R/R FL. One fatal adverse event (AE) occurred: squamous cell carcinoma in a CLL patient with prior squamous cell carcinoma. Serious AEs were reported in 22 (49%) CLL/SLL and 12 (33%) R/R FL patients.Common (>20%) any-grade AEs reported in CLL/SLL patients were upper respiratory tract infection (URTI; 49%), neutropenia (42%), contusion (33%), diarrhea (27%), cough (27%), fatigue (27%), and pyrexia (22%); and in FL patients were URTI (39%), con...

No abstract

The use of pulmonary artery catheters is under debate yet again. We look at two recent trials evaluating their impact on mortality. Our suspicions regarding obesity are proven and we also look at a simple, cost effective method of reducing ventilator-associated pneumonia. Finally, an intervention to improve the poor outcome associated with out-of hospital cardiac arrests is evaluated. A dying Swan: FACTT or fiction?The invention of the pulmonary artery catheter (PAC) 38 years ago by Drs Jeremy Swan and William Ganz was embraced by the medical world wholly and enthusiastically. It was presumed that the increased information provided would help deliver a more tailored and scientific approach to our critically unwell patients. However, concerns regarding their usefulness and safety are increasingly evident [1], and, with the development of alternative tools to calculate haemodynamic parameters, the use of the PAC is dwindling.The latest study to question their use compares PAC to central venous catheter (CVC) guided therapy in the management of 1,000 patients with newly established acute lung injury in a multi-centre prospective randomised trial [2]. This 'Fluid and Catheter Treatment Trial' (FACTT) assessed 60 day mortality, fluid balance, ventilator-free days, intensive therapy unit (ITU) length of stay and complication rates. Catheter-derived haemodynamic parameters and clinical measures were used in conjunction with explicit protocols to guide fluid, inotrope and diuretic management.Mortality rates were similar in both groups (27.4% PAC and 26.3% CVC), as were the number of ventilator-free days during the first 28 days (mean, 13.2 and 13.5, respectively). Fluid balance was similar in both groups, as was the incidence and duration of any type of organ failure. ITU stay was reduced in the CVC group, although the authors do acknowledge the mere presence of a PAC in a patient may have prevented discharge from ITU to a ward, thus causing erroneous results.Complication rates for both groups were similar per catheter insertion. However, PAC patients, in whom a CVC may have been placed once haemodynamically stable, received 50% more catheters, thus increasing the total number of complications, mostly arrhythmias, in this group.Is the 'Swan' destined for extinction? Proponents of PAC will point out that the conclusion only applies to a relatively young (median age 50 years), medical ITU population and excluded the majority of the 11,511 patients screened. These proponents will favour the study by Friese and colleagues [3], who scrutinised the American National Trauma Data Bank in a retrospective database analysis to assess the role of PACs on mortality in adult trauma patients admitted to ITU over an eight year period.The 53,312 patients were initially divided into two groups: those that received a PAC as part of their management (4%) and those that did not. Subsequently, they were divided according to age, Injury Severity Score and initial base deficit.Unsurprisingly, a higher use of PACs and a greater mortalit...