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Background In the era of widespread rituximab use for Waldenstrm's macro globulinaemia, new treatment options for patients with rituximab-refractory disease are an important clinical need. Ibrutinib has induced durable responses in previously treated patients with Waldenstrm's macro globulinaemia. We assessed the effi cacy and safety of ibrutinib in a population with rituximab-refractory disease. Methods This multicentre, open-label substudy was done at 19 sites in seven countries in adults aged 18 years and older with confi rmed Waldenstrm's macro globulinaemia, refractory to rituximab and requiring treatment. Disease refractory to the last rituximab-containing therapy was defi ned as either relapse less than 12 months since last dose of rituximab or failure to achieve at least a minor response. Key exclusion criteria included: CNS involvement, a stroke or intracranial haemorrhage less than 12 months before enrolment, clinically signifi cant cardiovascular disease, hepatitis B or hepatitis C viral infection, and a known bleeding disorder. Patients received oral ibrutinib 420 mg once daily until progression or unacceptable toxicity. The substudy was not prospectively powered for statistical comparisons, and as such, all the analyses are descriptive in nature. This study objectives were the proportion of patients with an overall response, progression-free survival, overall survival, haematological improvement measured by haemoglobin, time to next treatment, and patient-reported outcomes according to the Functional Assessment of Cancer TherapyAnemia (FACT-An) and the Euro Qol 5 Dimension Questionnaire (EQ-5D-5L). All analyses were per protocol. The study is registered at ClinicalTrials. gov, number NCT02165397, and follow-up is ongoing but enrolment is complete. Findings Between Aug 18, 2014, and Feb 18, 2015, 31 patients were enrolled. Median age was 67 years (IQR 58-74); 13 (42%) of 31 patients had high-risk disease per the International Prognostic Scoring System Waldenstrm Macroglobulinaemia, median number of previous therapies was four (IQR 2-6), and all were rituximab-refractory. At a median follow-up of 18.1 months (IQR 17.5-18.9), the proportion of patients with an overall response was 28 [90%] of 31 (22 [71%] of patients had a major response), the estimated 18 month progression-free survival rate was 86% (95% CI 66-94), and the estimated 18 month overall survival rate was 97% (95% CI 79-100). Baseline median haemoglobin of 10.3 g/dL (IQR 9.3-11.7) increased to 114 mu g/dL (10.9-12.4) after 4 weeks of ibrutinib treatment and reached 127 g/dL (11.8-13.4) at week 49. A clinically meaningful improvement from baseline in FACT-An score, anaemia subscale score, and the EQ-5D-5L were reported at all post-baseline visits. Time to next treatment will be presented at a later date. Common grade 3 or worse adverse events included neutropenia in four patients (13%), hypertension in three patients (10%), and anaemia, thrombocytopenia, and diarrhoea in two patients each (6%). Serious adverse events occurred in ten patients (32%) and were most often infections. Five (16%) patients discontinued ibrutinib: three due to progression and two due to adverse events, while the remaining 26 [84%] of patients are continuing ibrutinib at the time of this report. Interpretation The sustained responses and median progression-free survival time, combined with a manageable toxicity profi le observed with single-agent ibrutinib indicate that this chemotherapy-free approach is a potential new treatment choice for patients who had heavily pretreated, rituximab-refractory Waldenstrm's macro globulinaemia.

This article is based upon an SCI Model Project, funded by the American Association of Spinal Cord Injury Nurses (AASCIN). The purpose of this project was to develop a model to validate theoretical and practical knowledge of Registered Nurses and Licensed Practical Nurses/Licensed Vocational Nurses in an SCI rehabilitation setting. The investigators were direct care providers in a 68 bed SCI rehabilitation service at the James A. Haley Veterans Hospital in Tampa, Florida. The theoretical framework was based upon three aspects: Competency Validation, Theoretical Knowledge, and Practical Knowledge. Competency Validation was directed towards incorporating the elements of assessment, maintenance, demonstration, and improvement of competencies on an ongoing basis. Theoretical knowledge encompassed the cognitive and psychomotor aspects of SCI nursing, and Practical Knowledge highlighted the application of principles of caregiving. Two instruments were developed to harmonize theoretical and practical dimensions for competency validation: SCI Knowledge/Skill Appraisal (SKA) and Expertise in SCI Nursing Practice (ESNP). The purpose of this project was to design a model for validating theoretical and practical knowledge of Registered Nurses (RN's) and Licensed Practical Nurses/Licensed Vocational Nurses (LPN/LVN's) in an SCI rehabilitation setting. The investigators were direct care Licensed Practical Nurses/Licensed Vocational Nurses (LPN/LVN's) in an SCI rehabilitation setting. The investigators were direct care providers in a 68 bed spinal cord injury (SCI) rehabilitation service at the James A. Haley Veterans Hospital in Tampa, Florida.

Purpose: Marginal zone lymphoma (MZL) is an uncommon non–Hodgkin lymphoma with malignant cells that exhibit a consistent dependency on B-cell receptor signaling. We evaluated the efficacy and safety of zanubrutinib, a next-generation selective Bruton tyrosine kinase inhibitor, in patients with relapsed/refractory (R/R) MZL. Patients and Methods: Patients with R/R MZL were enrolled in the phase II MAGNOLIA (BGB-3111–214) study. The primary endpoint was overall response rate (ORR) as determined by an independent review committee (IRC) based on the Lugano 2014 classification. Results: Sixty-eight patients were enrolled. After a median follow-up of 15.7 months (range, 1.6 to 21.9 months), the IRC-assessed ORR was 68.2% and complete response (CR) was 25.8%. The ORR by investigator assessment was 74.2%, and the CR rate was 25.8%. The median duration of response (DOR) and median progression-free survival (PFS) by independent review was not reached. The IRC-assessed DOR rate at 12 months was 93.0%, and IRC-assessed PFS rate was 82.5% at both 12 and 15 months. Treatment was well tolerated with the majority of adverse events (AE) being grade 1 or 2. The most common AEs were diarrhea (22.1%), contusion (20.6%), and constipation (14.7%). Atrial fibrillation/flutter was reported in 2 patients; 1 patient had grade 3 hypertension. No patient experienced major hemorrhage. In total, 4 patients discontinued treatment due to AEs, none of which were considered treatment-related by the investigators. Conclusions: Zanubrutinib demonstrated high ORR and CR rate with durable disease control and a favorable safety profile in patients with R/R MZL.

Patients with Waldenström macroglobulinemia (WM) lacking activating mutations in the MYD88 gene (MYD88WT) have demonstrated relatively poor outcomes to ibrutinib monotherapy, with no major responses reported in a phase 2 pivotal study. Zanubrutinib is a novel, selective Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target activity. The ASPEN study consisted of a randomized comparison of zanubrutinib and ibrutinib efficacy and safety in patients with WM who have the MYD88 mutation, as well as a separate cohort of patients without MYD88 mutation (MYD88WT) or with unknown mutational status who received zanubrutinib. Results from the latter single-arm cohort are reported herein. Efficacy endpoints included overall, major and complete (CR) or very good partial response (VGPR) rates, progression-free survival (PFS), duration of response (DOR), and overall survival (OS). Twenty-eight patients (23 relapsed/refractory; 5 treatment-naïve) were enrolled, including 26 with centrally confirmed MYD88WT disease and 2 with unknown MYD88 mutational status. At a median follow-up of 17.9 months, 7 of 26 MYD88WT patients (27%) had achieved a VGPR and 50% a major response (partial response or better); there were no CRs. At 18 months, the estimated PFS and OS rates were 68% and 88%, respectively, while the median DOR had not been reached. Two patients discontinued zanubrutinib due to adverse events. Treatment-emergent hypertension, atrial fibrillation, and major hemorrhages were reported in 3, 1 and 2 patients (including 1 concurrent with enoxaparin therapy), respectively. Results of this substudy demonstrate that zanubrutinib monotherapy can induce high quality responses in patients with MYD88WT WM. This trial is registered on www.clinicaltrials.gov as NCT #03053440.