Bruton tyrosine kinase inhibitors for the frontline treatment of chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (cll) is the most commonly diagnosed adult leukemia in Canada. Biologic heterogeneity of cll between patients results in variable disease trajectories and responses to therapy. Notably, compared with patients lacking high-risk features, those with such features-such as deletions in chromosome 17p, aberrations in the TP53 gene, or unmutated immunoglobulin heavy chain variable region genes-experience inferior outcomes and responses to standard chemoimmunotherapy. Novel agents that target the B cell receptor signalling pathway, such as Bruton tyrosine kinase (btk) inhibitors, have demonstrated clinical efficacy and safety in patients with treatment-naïve cll, particularly those with high-risk features. However, given the current lack of head-to-head trials comparing btk inhibitors, selection of the optimal btk inhibitor for patients with cll is unclear and requires consideration of multiple factors. In the present review, we focus on the efficacy, safety, and pharmacologic features of the btk inhibitors that are approved or under clinical development, and we discuss the practical considerations for the use of those agents in the Canadian treatment landscape.

Canadian perspective on managing multiple myeloma during the COVID-19 pandemic: lessons learned and future considerations.

The coronavirus disease 2019 (covid-19) pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 has necessitated changes to the way patients with chronic diseases are managed. Given that patients with multiple myeloma are at increased risk of covid-19 infection and related complications, national bodies and experts around the globe have made recommendations for risk mitigation strategies for those vulnerable patients. Understandably, because of the novelty of the virus, many of the proposed risk mitigation strategies have thus far been reactionary and cannot be supported by strong evidence. In this editorial, we highlight some of the risk mitigation strategies implemented at our institutions across Canada during the first wave of covid-19, and we discuss the considerations that should be made when managing patients during the second wave and beyond.

Highlights from ASCO 2020: updates on the treatment of chronic lymphocytic leukemia.

Because of the global coronavirus pandemic, the 2020 annual scientific meeting of the American Society of Clinical Oncology took place virtually, 29-30 May. At the meeting, results from key studies about the treatment of chronic lymphocytic leukemia (cll) were disseminated. Studies examined the efficacy and safety of ibrutinib, acalabrutinib, zanubrutinib, and venetoclax as monotherapy or in combination with novel agents for patients with treatment-naïve and relapsed or refractory cll. Our meeting report describes the foregoing studies and presents interviews with investigators and commentaries by Canadian hematologists about potential effects on Canadian practice.

Updates from the American Society of Hematology 2019 annual meeting: practice-changing studies in treatment-naïve chronic lymphocytic leukemia.

The 2019 annual meeting of the American Society of Hematology took place 7-10 December in Orlando, Florida. At the meeting, results from key studies in treatment-naïve chronic lymphocytic leukemia (cll) were presented. Of those studies, phase iii oral presentations focused on the efficacy and safety of therapy with inhibitors of Bruton tyrosine kinase (btk) and Bcl-2. One presentation reported updated results of the Eastern Cooperative Oncology Group 1912 trial comparing the efficacy and safety of ibrutinib-rituximab with that of fludarabine-cyclophosphamide-rituximab in patients less than 70 years of age with cll. A second presentation reported interim results of the elevate tn trial, which is investigating the efficacy and safety of acalabrutinib-obinutuzumab or acalabrutinib monotherapy compared with chlorambucil-obinutuzumab. A third presentation reported on the single-agent zanubrutinib arm of the sequoia trial in patients with del(17p). The final presentation constituted a data update from the cll14 trial, which is evaluating fixed-duration venetoclax-obinutuzumab compared with chlorambucil-obinutuzumab, including the association of minimal residual disease status with progression-free survival. Our meeting report describes the foregoing studies and presents interviews with investigators and commentaries by Canadian hematologists about potential effects on Canadian practice.

Updates from the 2019 American Society of Clinical Oncology and European Hematology Association annual meetings: a Canadian perspective on high-risk cytogenetics in multiple myeloma.

The 2019 annual meetings of the American Society of Clinical Oncology and the European Hematology Association took place, respectively, in Chicago, Illinois, 31 May-4 June, and in Amsterdam, Netherlands, 13-16 June. At the meetings, results from key studies on the treatment of patients with relapsed or refractory multiple myeloma with high-risk cytogenetics were presented. Our meeting report describes those studies and includes interviews with investigators and commentaries by Canadian hematologists about the potential impact on Canadian practice.

Characteristics predicting outcomes of allogeneic stem-cell transplantation in relapsed acute myelogenous leukemia.

BACKGROUND: Allogeneic hematopoietic stem-cell transplantation (ahsct) is associated with significant morbidity and mortality, but it can cure carefully selected patients with acute myeloid leukemia (aml) in second remission (cr2). In a cohort of patients with aml who underwent ahsct in cr2, we determined the pre-transplant factors that predicted for overall survival (os), relapse, and non-relapse mortality. We also sought to validate the prognostic risk groups derived by Michelis and colleagues in this independent population. METHODS: In a retrospective chart review, we obtained data for 55 consecutive patients who underwent ahsct for aml in cr2. Hazard ratios were used to describe the independent effects of pre-transplant variables on outcome, and Kaplan-Meier curves were used to assess outcomes in the three prognostic groups identified by Michelis and colleagues. RESULTS: At 1, 3, and 5 years post-transplant, os was 60%, 45.5%, and 37.5% respectively. Statistically significant differences in os, relapse mortality, and non-relapse mortality were not identified between the prognostic risk groups identified by Michelis and colleagues. Women were less likely than men to relapse, and a modified European Society for Blood and Marrow Transplantation (mebmt) score of 3 or less was associated with a lower non-relapse mortality. CONCLUSIONS: The 37.5% 5-year os in this cohort suggests that, compared with other options, ahsct offers patients with aml in cr2 a better chance of cure. Our study supports the use of the mebmt score to predict non-relapse mortality in this population.

Recovery of adrenal function after chronic secondary adrenal insufficiency in patients with hypopituitarism.

OBJECTIVE: Previous studies have reported recovery of secondary adrenal insufficiency (SAI) in patients with pituitary disorders, generally immediately after pituitary surgery; however, data regarding recovery of long-term SAI are lacking. We conducted a study to assess the longer term recovery rate of SAI in patients with pituitary disorders. METHODS: We identified all SAI patients in the Halifax Neuropituitary Database from 1 November 2005 to 30 September 2014, who had required glucocorticoid therapy for ≥3 months, and had a minimum follow-up of 6 months. Patients with ACTH-secreting adenomas, those receiving glucocorticoids only in the routine peri-operative period for pituitary surgery and those on glucocorticoids for nonpituitary conditions were excluded. SAI was defined as either basal serum cortisol < 130 nm and/or a subnormal cortisol response to ACTH-(1-24) stimulation test or insulin tolerance test response. RESULTS: Fifty-one patients fulfilled the criteria. Nine (17·6%) patients had complete recovery of SAI over a median of 20 months (range: 8-51) after initiating glucocorticoid replacement. Patients with smaller tumour size had increased likelihood of hypothalamic-pituitary-adrenal (HPA) axis recovery, whereas those with secondary hypogonadism or growth hormone deficiency were less likely to recover. Those with initial cortisol >175 nm had an almost one in two chance of recovery. CONCLUSION: Results from our study show that approximately one in six patients with SAI recover adrenal function, even up to 5 years after diagnosis. We recommend that patients with SAI undergo regular testing to assess recovery in order to prevent unnecessary glucocorticoid therapy.

Outcomes of patients treated through the Canadian Fabry disease initiative.

BACKGROUND: The Canadian Fabry disease initiative (CFDI) tracks outcomes of subjects with Fabry disease treated enzyme replacement therapy (ERT) given to subjects who meet evidence-based treatment guidelines and cardiovascular risk factor modification. METHODS: We report 5 year follow-up data on 362 subjects for a composite endpoint (death, neurologic or cardiovascular events, development of end-stage renal disease or sustained increase in serum creatinine of 50% from baseline). RESULTS: At enrollment, 86 subjects had previously received ERT (Cohort 1a) and 67 subjects were newly started (Cohort 1b) and randomized to agalsidase alfa or agalsidase beta. 209 subjects did not initially meet ERT criteria (Cohort 1c), 25 of whom met ERT criteria in follow-up and were moved to Cohort 1b (total N=178 ERT treated subjects). Use of supportive therapies such as aspirin (78%), renin-angiotensin blockade (59%), and statins (55%) was common in ERT treated subjects. In Cohort 1a, 32 subjects met the composite endpoint with 8 deaths. In Cohort 1b, 16 subjects met the composite endpoint with 1 death. Cohort 1b had fewer clinical events than Cohort 1a (p=0.039) suggesting that the treatment protocol was effective in targeting subjects at an earlier stage. 19.4% of Cohort 1b subjects on agalsidase alfa and 13.3% on agalsidase beta had a clinical event (p=0.57). 10 Cohort 1c subjects had clinical events, none of which would have been prevented by earlier use of ERT. CONCLUSIONS: Cardiovascular risk factor modification and targeted use of ERT reduce the risk of adverse outcomes related to Fabry disease.

Persistency of Pseudomonas aeruginosa in sputum cultures and clinical outcomes in adult patients with cystic fibrosis.

Our objective was to describe the natural history of infection with transmissible and unique strains of P. aeruginosa (PA) in adult CF patients and to determine if clearance of PA from sputum was associated with an improvement in clinical status. This was a 3-year prospective cohort study of adult patients with CF. Sputum was collected at baseline and annually. Rate of decline of FEV1, BMI, exacerbation rate, and time to death or transplant were compared between patients who cleared PA versus those in whom PA was persistent. A total of 373 patients were included in the study, 75% were infected with PA at baseline; 24% were infected with transmissible strains and 51% with unique strains. Patients infected with unique strains were more likely to clear PA from their sputum over 3 years compared to those infected with transmissible strains (19% vs 10%, P=0.05). Declines in FEV1 and rates of pulmonary exacerbations, deaths, or lung transplants were not different between patients who cleared PA compared to those who remained persistently infected. No clinical benefit was identified in patients who cleared PA from sputum compared to those who remained persistently infected.

The antibacterial effect of photodynamic therapy in dental plaque-derived biofilms.

BACKGROUND AND OBJECTIVE: Photodynamic therapy has been advocated as an alternative to antimicrobial agents to suppress subgingival species and to treat periodontitis. Bacteria located within dense biofilms, such as those encountered in dental plaque, have been found to be relatively resistant to antimicrobial therapy. In the present study, we investigated the ability of photodynamic therapy to reduce the number of bacteria in biofilms by comparing the photodynamic effects of methylene blue on human dental plaque microorganisms in the planktonic phase and in biofilms. MATERIAL AND METHODS: Dental plaque samples were obtained from 10 subjects with chronic periodontitis. Suspensions of plaque microorganisms from five subjects were sensitized with methylene blue (25 microg/mL) for 5 min then exposed to red light. Multispecies microbial biofilms developed from the same plaque samples were also exposed to methylene blue (25 microg/mL) and the same light conditions as their planktonic counterparts. In a second set of experiments, biofilms were developed with plaque bacteria from five subjects, sensitized with 25 or 50 microg/mL of methylene blue and then exposed to red light. After photodynamic therapy, survival fractions were calculated by counting the number of colony-forming units. RESULTS: Photodynamic therapy killed approximately 63% of bacteria present in suspension. By contrast, in biofilms, photodynamic therapy had much less of an effect on the viability of bacteria (32% maximal killing). CONCLUSION: Oral bacteria in biofilms are affected less by photodynamic therapy than bacteria in the planktonic phase. The antibacterial effect of photodynamic therapy is reduced in biofilm bacteria but not to the same degree as has been reported for treatment with antibiotics under similar conditions.

Prevalence of associated deformities and hip pain in patients with cam-type femoroacetabular impingement.

Femoroacetabular impingement is a cause of hip pain in adults and is potentially a precursor of osteoarthritis. Our aim in this study was to determine the prevalence of bilateral deformity in patients with symptomatic cam-type femoroacetabular impingement as well as the presence of associated acetabular abnormalities and hip pain. We included all patients aged 55 years or less seen by the senior author for hip pain, with at least one anteroposterior and lateral pelvic radiograph available. All patients with dysplasia and/or arthritis were excluded. A total of 113 patients with a symptomatic cam-impingement deformity of at least one hip was evaluated. There were 82 men and 31 women with a mean age of 37.9 years (16 to 55). Bilateral cam-type deformity was present in 88 patients (77.8%) while only 23 of those (26.1%) had bilateral hip pain. Painful hips had a statistically significant higher mean alpha angle than asymptomatic hips (69.9 degrees vs 63.1 degrees , p < 0.001). Hips with an alpha angle of more than 60 degrees had an odds ratio of being painful of 2.59 (95% confidence interval 1.32 to 5.08, p = 0.006) compared with those with an alpha angle of less than 60 degrees . Of the 201 hips with a cam-impingement deformity 42% (84) also had a pincer deformity. Most patients with cam-type femoroacetabular impingement had bilateral deformities and there was an associated acetabular deformity in 84 of 201 patients (42%). This information is important in order to define the natural history of these deformities, and to determine treatment.

Predictors of pulmonary exacerbations in patients with cystic fibrosis infected with multi-resistant bacteria.

BACKGROUND: This study examined characteristics of adult and adolescent patients with cystic fibrosis (CF) to determine factors associated with an increased risk of pulmonary exacerbations. METHODS: 249 patients with CF infected with multidrug resistant bacteria were recruited and prospectively followed for up to 4.5 years until they experienced a pulmonary exacerbation severe enough to require intravenous antibiotics. Multivariable regression analyses were used to compare the characteristics of patients who experienced an exacerbation with those who did not. RESULTS: 124 of the 249 patients (50%) developed a pulmonary exacerbation during the first year and 154 (62%) experienced an exacerbation during the 4.5 year study period. Factors predictive of exacerbations in a multivariable survival model were younger age (OR 0.98, 95% CI 0.96 to 0.99), female sex (OR 1.45, 95% CI 1.07 to 1.95), lower forced expiratory volume in 1 second (FEV(1)) (OR 0.98, 95% CI 0.97 to 0.99), and a previous history of multiple pulmonary exacerbations (OR 3.16, 95% CI 1.93 to 5.17). Chronic use of inhaled corticosteroids was associated with an increased risk of exacerbation (OR 1.92, 95% CI 1.00 to 3.71) during the first study year. CONCLUSIONS: Patients who experience pulmonary exacerbations are more likely to be younger, female, using inhaled steroids, have a lower FEV(1), and a history of multiple previous exacerbations. It is hoped that knowledge of these risk factors will allow better identification and closer monitoring of patients who are at high risk of exacerbations.

Sputum versus bronchoscopy for diagnosis of Pseudomonas aeruginosa biofilms in cystic fibrosis.

The present authors hypothesised that bronchoscopy with protected specimen brush may sample biofilm-forming bacteria adherent to the airway wall, whereas traditional sputum collection may not. Pseudomonas aeruginosa obtained from sputum, bronchoalveolar lavage and protected brush, taken from the right upper lung bronchus of 12 adult patients with cystic fibrosis, were compared. Retrieved bacteria were genotyped, and grown in planktonic cultures and as biofilms, and susceptibilities to individual antibiotics and to antibiotic combinations were determined. Bacterial cultures obtained using bronchoscopy did not yield any new strains of bacteria that were not also found in sputum. A total of 10 patients (83%) had a single strain of P. aeruginosa found using sputum, bronchoalveolar lavage and protected brush techniques, and two patients (17%) had two strains recovered in sputum, but only one strain was recovered using bronchoscopic techniques. Susceptibility to single antibiotics and to antibiotic combinations were not different between planktonically or biofilm-grown bacteria derived from sputum, as compared to those obtained by bronchoalveolar lavage and protected brush. In conclusion, sputum collection provides as much information as bronchoscopy for characterising the genotype and antibiotic susceptibility of chronic Pseudomonas aeruginosa infection in patients with stable cystic fibrosis.