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Background: Inhibitors of Bruton tyrosine kinase (BTK) have established therapeutic activity in patients with WM. Zanubrutinib, a potent and selective BTK inhibitor was evaluated in a phase 1/2 study in treatment- naive (TN) and relapsed/refractory (R/R) patients with WM. Aim(s): To examine the safety and preliminary efficacy of single-agent zanubrutinib in patients with TN or R/R WM. Method(s): Patients had TN or R/R WM and required treatment as per IWWM criteria. Treatment consisted of oral zanubrutinib at 160 mg twice daily (n = 50) or 320 mg once daily (n = 23) until disease progression or unacceptable toxicity. Efficacy endpoints included the proportion of patients achieving a complete response (CR) or very good partial response (VGPR) in accordance with IWWM-6 criteria. Efficacy analyses were conducted on the efficacy evaluable patients. Result(s): Between September 2014 and August 2018, 77 patients with WM (24 TN and 53 R/R) began treatment with zanubrutinib (54% were aged > 65 and 21% > 75 years). A total of 73 out of 77 patients were considered efficacy evaluable. At a median follow up of 32.7 months, 73% remain on treatment. Reasons for treatment discontinuation included adverse events (AEs) in 13% of patients (only one treatment-related), disease progression (10.4%) and other (3.9%). Five grade 5 AEs occurred: abdominal sepsis, septic arthritis, scedosporium infection, (patient with prior history of scedosporium abscess) bronchiectasis, and gastric adenocarcinoma (none related). Results are presented for TN and R/R patients combined. The overall response rate was 96% and the VGPR/CR rate was 45% (Table). The rates of VGPR/CR increased over time; 22% at 6 months, 33% at 12 months and 45% at 24 months. The VGPR/CR rate was the highest among patients with the MYD88L265P/CXCR4WT genotype (59%). Of the patients with known MYD88WT, 62.5% had a major response. The rate of progression-free and overall survival at 3 years were 81% and 85%, respectively. The most c

Cytomegalovirus (CMV) viraemia continues to be a frequent complication in the post-haemopoietic stem cell transplantation period despite a low incidence of CMV end-organ disease. Several significant advances in the understanding and management of CMV infection have occurred in the last few years including improved diagnostics, monitoring of CMV immunity, availability of novel anti-CMV drugs, and emerging use of immunotherapies including CMV-specific T-cell infusions. In addition to reviewing these advances we also explore some of the more practical prescribing issues of the older and newer CMV drugs including cost, toxicity and drug interactions to help clinicians navigate this new era of CMV management.

Zanubrutinib is a potent and highly selective inhibitor of Bruton tyrosine kinase (BTK). In this first-in-human, open-label, multicenter, phase 1 study, patients in part 1 (3 1 3 dose escalation) had relapsed/refractory B-cell malignancies and received zanubrutinib 40, 80, 160, or 320 mg once daily or 160 mg twice daily. Part 2 (expansion) consisted of disease-specific cohorts, including treatment-naive or relapsed/refractory chronic lymphocytic leukemia/ small lymphocytic lymphoma (CLL/SLL). The primary end points were safety and tolerability, and definition of the maximum tolerated dose (part 1). Additional end points included pharmacokinetics/pharmacodynamics and preliminary efficacy. Reported herein are results from 144 patients enrolled in the dose-finding and CLL/SLL cohorts. No dose-limiting toxicities occurred in dose escalation. Median BTK occupancy in peripheral blood mononuclear cells was >95% at all doses. Sustained complete (>95%) BTK occupancy in lymph node biopsy specimens was more frequent with 160 mg twice daily than 320 mg once daily (89% vs 50%; P 5 .0342). Consequently, 160 mg twice daily was selected for further investigation. With median follow-up of 13.7 months (range, 0.4-30.5 months), 89 CLL/SLL patients (94.7%) remain on study. Most toxicities were grade 1/2; neutropenia was the only grade 3/4 toxicity observed in >2 patients. One patient experienced a grade 3 subcutaneous hemorrhage. Among 78 efficacy-evaluable CLL/SLL patients, the overall response rate was 96.2% (95% confidence interval, 89.2-99.2). Estimated progression-free survival at 12 months was 100%. Zanubrutinib demonstrated encouraging activity in CLL/SLL patients, with a low incidence of major toxicities.Copyright © 2019 by The American Society of Hematology

Background: Zanubrutinib (zanu) is a potent, specific and irreversible oral BTK inhibitor. In Phase 1 testing, we have demonstrated that high plasma concentrations can be safely achieved, resulting in complete and sustained BTK inhibition in blood and lymph nodes. Early clinical data from an ongoing Phase 1 trial has shown single-agent zanu to be safe and efficacious for the treatment of pts with chronic lymphocytic leukemia (Seymour 2017), WM (Trotman 2017), and other non-Hodgkin lymphomas (Tam 2017). Aim(s): Report updated safety and efficacy data from WM pts with a median follow-up of >1 year in this Phase 1 trial. Method(s): This is an open-label, multi-center, dose-finding Phase I study of zanu in pts with B-cell malignancies, with indication-specific expansion cohorts: reported here are data from 67 WM pts enrolled as of 3 Nov 2017. Pts received doses of zanu ranging from 40 mg once daily to the final RP2D of 160 mg twice daily until disease progression (PD) or unacceptable toxicity. Pts were assessed by IgM monthly with full assessment of extramedullary disease every 3 months. Result(s): 67 pts with WM were enrolled and evaluable for safety; 51 pts were evaluable for efficacy, excluding those with <12 weeks follow-up (n=13) or IgM <5 g/L at baseline (n=3). The 67 pts included 21 treatmentnative (TN) and 46 relapsed/refractory (R/R; 1-8 prior therapies) and median follow-up 15.5 months (range, 0.1-37.6). The most frequent AEs (>=15%, all Gr 1-2 but 1) were petechia/purpura/contusion (37%), upper respiratory tract infection (34%), constipation (18%) and diarrhea (18%). Gr 3-4 AEs included anemia (8%), headache (2%), and diarrhea (2%). Serious AEs (SAEs) were seen in 22 pts (33%) with 5 individual pts (8%) considered related to zanu; febrile neutropenia, colitis, atrial fibrillation, hemothorax (spontaneous), and headache. There was 1 fatal event from worsening preexisting bronchiectasis in a pt with VGPR. Atrial fibrillation/flutter was experienced by 4 pts (6%

Background: Bruton's tyrosine kinase (BTK) plays a critical role in B-cell receptor signaling, which mediates B-cell proliferation, migration and adhesion. Zanubrutinib is a potent, selective and irreversible BTK inhibitor. It has demonstrated profound BTK inhibition with minimal inhibition of offtarget kinases such as EGFR, ITK, JAK3, HER2, and TEC, providing a good scientific rationale for a reduced toxicity profile. Aim(s): To demonstrate the safety profile of zanubrutinib. Method(s): Safety data from patients (pts) in 6 ongoing zanubrutinib monotherapy studies were analyzed. All pts have been treated with >=1 dose of oral (po) zanubrutinib at 40 mg once-daily to 160 mg twice-daily (bid). The analysis included frequency and severity of adverse events (AEs), AEs of special interest, and AEs leading to treatment discontinuation. Result(s): A total of 424 pts were included in the pooled analysis, with a data cutoff date of September 15, 2017. The median age was 64 years (range 20- 87) and 71.9% were males. The median follow-up duration was 4.8 months (range 0.03-36.0). The most common (occurring in >=10% of pts) AEs were upper respiratory tract infection (23.8%), contusion (17.5%), diarrhea (14.2%), cough (13.0%), rash (12.7%), anemia (11.8%), and neutrophil count decreased (11.6%). Serious AEs (SAEs) were reported in 24.3%, including 7.5% that were assessed as related to zanubrutinib. The most common SAEs included pneumonia (3.5%), lung infection (1.7%) and febrile neutropenia (1.2%). AEs of special interest are shown in the Table 1. The most common bleeding events included contusion (17.5%) and hematuria (8.3%). Major hemorrhage, defined as serious or Grade >=3 bleeding of any site, or central nervous system bleeding of any grade included gastrointestinal hemorrhage, purpura (0.5% each), melena, hemorrhagic cystitis, hematuria, renal hematoma, cerebral hemorrhage and hemothorax (0.2% each). The median time to first major hemorrhage was 23 days (range 3-262). The f

Background: Zanubrutinib, an investigational BTK inhibitor, achieves high plasma concentrations and sustained complete BTK occupancy in blood and lymph nodes, with greater selectivity for BTK vs other TEC and EGFR family kinases in biochemical assays, and favorable pharmacokinetic/ pharmacodynamic properties in preclinical studies. Aim(s): To present updated zanubrutinib safety and efficacy data in patients (pts) with WM. Method(s): This is a global, open-label, multicenter, phase 1/2 study in pts with B-cell malignancies with indication-specific expansion cohorts. Pts received doses of zanubrutinib ranging from 40 mg once daily to the final recommended phase 2 dose of 160 mg twice daily or 320 mg once daily until disease progression (PD) or unacceptable toxicity. We report here on the 77 WM pts from the cohorts who had no prior BTK therapy. The primary endpoint is safety/tolerability. Secondary endpoints include response rate and PFS assessed by IRC. Result(s): As of September 16th, 2018, 77 pts with WM received zanubrutinib (Table). The most common (>15%) adverse events (AEs) of any grade were upper respiratory tract infection (46%), contusion (30%), cough (20%), headache (18%), back pain (17%), diarrhea (17%), urinary tract infection (16%), and constipation (16%). Grade >=3 AEs in >=5% of pts were neutropenia (10%) anemia (8%), hypertension (5%), and basal cell carcinoma (5%). The most common serious AEs were cellulitis (5%), pneumonia (4%), pyrexia (3%), febrile neutropenia (3%), and atrial fibrillation (3%). Sixteen pts discontinued treatment, 8 due to AE, 4 due to PD, 1 due to investigator decision, and 3 others (radiation therapy [n = 1], not compliant with taking drug [n = 2]). Five fatal AEs occurred: abdominal sepsis, septic arthritis, scedosporium infection, bronchiectasis, and gastric adenocarcinoma, of which one was considered related to treatment (septic arthritis) Regarding AEs of special interest with BTK inhibitor therapy, 2 pts (3%) had major haemo

BACKGROUND:This cross-sectional survey aimed to establish the prevalence of infectious diseases and vaccination uptake in long-term allogeneic hematopoietic stem cell transplants (HSCT) survivors in New South Wales, in order to reduce long-term post-HSCT morbidity and mortality and enhance long-term care. PATIENTS AND METHODS:Hematopoietic stem cell transplants survivors aged over 18 years and transplanted between 2000-2012 in New South Wales (NSW) were eligible to participate. Survivors self-completed the Sydney Post BMT Study survey, FACT-BMT (V4), Chronic Graft versus Host Disease (cGVHD) Activity Assessment Self Report, Lee Chronic GvHD Symptom Scale, DASS21, Post Traumatic Growth Inventory, and the Fear of Recurrence Scale. RESULTS:Of the 583 HSCT survivors contacted, 441 (78%) completed the survey. Respondents included 250 (57%) males and median age was 54 years (range 19-79 years). The median age at the time of transplant was 49 years (Range: 17-71), the median time since HSCT was 5 years (Range: 1-14) and 69% had cGVHD. Collectively, 41.7% of survivors reported a vaccine preventable disease (VPD) with the most common being influenza-like-illness (38.4%), varicella zoster/shingles (27.9%), pap smear abnormalities (9.8%), pneumococcal disease (5.1%), and varicella zoster (chicken pox) (4.6%). Only 31.8% had received the full post-HSCT vaccination schedule, and the majority (69.8%) of these had received the vaccines via their General Practitioner. cGVHD was not found to be a significant factor on multivariate analysis for those who were vaccinated. There was a trend toward lower vaccination rates in patients in a lower income strata. CONCLUSIONS:Vaccinating post-HSCT survivors to prevent infections and their consequences have an established role in post-HSCT care. Improving rates of post-HSCT vaccination should be a major priority for BMT units.