Management and use of healthcare resources in patients with chronic lymphocytic leukemia initiating venetoclax in routine clinical practice.

Venetoclax is a first-in-class B-cell lymphoma-2 (BCL-2) inhibitor approved as continuous monotherapy and in combination with rituximab as fixed-treatment duration for relapsed and refractory chronic lymphocytic leukemia (R/R CLL). DEVOTE was a 24-week, multicenter observational study (NCT03310190) evaluating the safety, healthcare resource utilization (HCRU) and health-related quality of life (HRQoL) of patients initiating venetoclax for R/R CLL in Canada. Overall, 89 patients received 1 dose of venetoclax; 80% had prior exposure (42% resistant) to ibrutinib. Biochemical tumor lysis syndrome (TLS) occurred in five patients. We observed differences in hospitalization across Canadian provinces including in patients at low risk for TLS with no clear impact on TLS incidence. Additionally, a rapid and sustained improvement in several domains of HRQoL was observed during venetoclax initiation. Early adoption of venetoclax was mainly for R/R CLL patients with few treatment options; nonetheless, acceptable toxicity and a positive impact on HRQoL were observed.

Impact of Fixed-Duration Oral Targeted Therapies on the Economic Burden of Chronic Lymphocytic Leukemia in Canada.

BACKGROUND: Continuous oral targeted therapies (OTT) represent a major economic burden on the Canadian healthcare system, due to their high cost and administration until disease progression/toxicity. The recent introduction of venetoclax-based fixed-duration combination therapies has the potential to reduce such costs. This study aims to estimate the prevalence and the cost of CLL in Canada with the introduction of fixed OTT. METHODS: A state transition Markov model was developed and included five health states: watchful waiting, first-line treatment, relapsed/refractory treatment, and death. The number of CLL patients and total cost associated with CLL management in Canada for both continuous- and fixed-treatment-duration OTT were projected from 2020 to 2025. Costs included drug acquisition, follow-up/monitoring, adverse event, and palliative care. RESULTS: The CLL prevalence in Canada is projected to increase from 15,512 to 19,517 between 2020 and 2025. Annual costs were projected at C$880.7 and C$703.1 million in 2025, for continuous and fixed OTT scenarios, respectively. Correspondingly, fixed OTT would provide a total cost reduction of C$213.8 million (5.94%) from 2020 to 2025, compared to continuous OTT. CONCLUSIONS: Fixed OTT is expected to result in major reductions in cost burden over the 5-year projection, compared to continuous OTT.

Canadian evidence-based guideline for frontline treatment of chronic lymphocytic leukemia: 2022 update.

Chronic lymphocytic leukemia (cll) is the most common adult leukemia in North America. In 2018, the first unified national guideline in Canada was developed for the front-line treatment of cll that helped guide treatment across the country. As an update in 2022, a group of clinical experts from across Canada came together to provide input and guidance that included new and innovative treatments and approaches that will continue to provide health care professionals with clear guidance on the first-line management of cll. Recommendations were provided in consensus based on available evidence for the first-line treatment of cll.

Canadian evidence-based guideline for treatment of relapsed/refractory chronic lymphocytic leukemia.

Following the recent publication of Canadian evidence-based guidelines for frontline treatment of chronic lymphocytic leukemia (CLL), the same group of clinicians developed guidelines for CLL in the relapsed/refractory (R/R) setting. The treatment of R/R CLL has changed significantly in the past few years, with many novel therapeutics available to hematologists across the country. These guidelines aim to standardize the management of CLL in the relapsed/refractory setting, using the best evidence currently available.

Low-dose trimethoprim-sulfamethoxazole for the treatment of Pneumocystis jirovecii pneumonia (LOW-TMP): protocol for a phase III randomised, placebo-controlled, dose-comparison trial.

INTRODUCTION: Pneumocystis jirovecii pneumonia (PJP) is an opportunistic infection of immunocompromised hosts with significant morbidity and mortality. The current standard of care, trimethoprim-sulfamethoxazole (TMP-SMX) at a dose of 15-20 mg/kg/day, is associated with serious adverse drug events (ADE) in 20%-60% of patients. ADEs include hypersensitivity reactions, drug-induced liver injury, cytopenias and renal failure, all of which can be treatment limiting. In a recent meta-analysis of observational studies, reduced dose TMP-SMX for the treatment of PJP was associated with fewer ADEs, without increased mortality. METHODS AND ANALYSIS: A phase III randomised, placebo-controlled, trial to directly compare the efficacy and safety of low-dose TMP-SMX (10 mg/kg/day of TMP) with the standard of care (15 mg/kg/day of TMP) among patients with PJP, for a composite primary outcome of change of treatment, new mechanical ventilation, or death. The trial will be undertaken at 16 Canadian hospitals. Data will be analysed as intention to treat. Primary and secondary outcomes will be compared using logistic regression adjusting for stratification and presented with 95% CI. ETHICS AND DISSEMINATION: This study has been conditionally approved by the McGill University Health Centre; Ethics approval will be obtained from all participating centres. Results will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT04851015.

Genetic interactions between Pax9 and Msx1 regulate lip development and several stages of tooth morphogenesis.

Developmental abnormalities of craniofacial structures and teeth often occur sporadically and the underlying genetic defects are not well understood, in part due to unknown gene-gene interactions. Pax9 and Msx1 are co-expressed during craniofacial development, and mice that are single homozygous mutant for either gene exhibit cleft palate and an early arrest of tooth formation. Whereas in vitro assays have demonstrated that protein-protein interactions between Pax9 and Msx1 can occur, it is unclear if Pax9 and Msx1 interact genetically in vivo during development. To address this question, we compounded the Pax9 and Msx1 mutations and observed that double homozygous mutants exhibit an incompletely penetrant cleft lip phenotype. Moreover, in double heterozygous mutants, the lower incisors were consistently missing and we find that transgenic BMP4 expression partly rescues this phenotype. Reduced expression of Shh and Bmp2 indicates that a smaller "incisor field" forms in Pax9(+/-);Msx1(+/-) mutants, and dental epithelial growth is substantially reduced after the bud to cap stage transition. This defect is preceded by drastically reduced mesenchymal expression of Fgf3 and Fgf10, two genes that encode known stimulators of epithelial growth during odontogenesis. Consistent with this result, cell proliferation is reduced in both the dental epithelium and mesenchyme of double heterozygous mutants. Furthermore, the developing incisors lack mesenchymal Notch1 expression at the bud stage and exhibit abnormal ameloblast differentiation on both labial and lingual surfaces. Thus, Msx1 and Pax9 interact synergistically throughout lower incisor development and affect multiple signaling pathways that influence incisor size and symmetry. The data also suggest that a combined reduction of PAX9 and MSX1 gene dosage in humans may increase the risk for orofacial clefting and oligodontia.

Examining Treatment Patterns and Real-World Outcomes in Chronic Lymphocytic Leukemia Using Administrative Data in Ontario.

Information on the real-world experience of Canadians diagnosed with chronic lymphocytic leukemia (CLL) is limited. This study was conducted to report treatment patterns and outcomes of CLL using Ontario administrative data. A retrospective cohort study was conducted in patients diagnosed with CLL between 1 January 2010 and 31 December 2017 identified in the Ontario Cancer Registry (OCR). Data were accessed using the Institute of Clinical Evaluative Sciences (ICES), which collects various population-level health information. In the Ontario Cancer Registry, 2887 CLL patients receiving treatment and diagnosed between 2010-2017 were identified. Fludarabine, cyclophosphamide and rituximab (FCR) chemoimmunotherapy was most frequently used as a first line, but use declined since ibrutinib and obinutuzumab combinations were funded in 2015. In patients treated with frontline FCR, survival at year one was 89% pre-2015 and 96% post-2015; at year four, survival was 73% and 87%, respectively. Survival in patients treated with frontline chlorambucil was 76% pre-2015 and 75% post-2015 in year 1, and 45% and 56% in year 3. Our analysis shows that, as the treatment landscape for CLL has shifted, use of newer and novel agents as a first line or earlier in the relapsed/refractory setting has resulted in improved survival outcomes.

Impact of Oral Targeted Therapy on the Economic Burden of Chronic Lymphocytic Leukemia in Canada.

Background: Continuous oral targeted therapy (OTT) for chronic lymphocytic leukemia (CLL) represents an effective therapy but also a major economic burden on the healthcare system. This study aimed to estimate future direct costs, along with the prevalence, of CLL in the era of continuous OTT in Canada. Methods: The economic burden of OTT was modelled and compared to chemoimmunotherapy (CIT), for CLL treatment. The burden was assessed/projected from 2011 to 2025. For the OTT scenario, CIT was considered the standard of care before 2015, while OTT was considered standard of care for patients with either unmutated immunoglobulin heavy-chain variable (IGHV) or del(17p)/TP53 mutations starting in 2015 and, from 2020 onwards, for all first-line treatments except for patients with mutated IGHV. A Markov model was developed including four health states: watchful-waiting, first-line treatment, relapse and death. Costs of therapy, follow-up/monitoring and adverse events were included. Key clinical parameters were extracted from pivotal clinical trials. Results: As incidence rates and rate of survival are increasing, the prevalence of CLL in Canada is projected to increase 1.8-fold, from 8301 patients in 2011 to 14,654 by 2025. Correspondingly, the total annual costs of CLL management are predicted to increase 15.7-fold, from $60.8 million to $957.5 million during that same period. Conclusions: Although OTT enhances survival for patients with CLL, it is nonetheless associated with an important economic burden due to the projected vast increase in costs from 2011 to 2025. Changes in clinical strategies, such as implementation of a fixed OTT treatment duration, could help alleviate financial burden.

SARS-CoV-2 in migrant worker dormitories: Geospatial epidemiology supporting outbreak management.

BACKGROUND: Migrant worker dormitories-residential complexes where 10-24 workers share living spaces-account for the majority of cases of SARS-CoV-2 infection in Singapore. To prevent overspill of transmission to the wider population, starting in early April 2020, residents were confined to their dormitories while measures were put in place to arrest the spread of infection. This descriptive study presents epidemiological data for a population of more than 60 000 migrant workers living in two barracks-style and four apartment-style dormitories located in western Singapore from April 3 to June 10, 2020. METHODS: Our report draws from data obtained over the first 50 days of outbreak management in order to describe SARS-CoV-2 transmission in high-density housing environments. Cumulative counts of SARS-CoV-2 cases and numbers of housing units affected were analyzed to report the harmonic means of harmonic means of doubling times and their 95% confidence intervals (CI). RESULTS: Multiple transmission peaks were identified involving at least 5467 cases of SARS-CoV-2 infection across six dormitories. Our geospatial heat maps gave an early indication of outbreak severity in affected buildings. We found that the number of cases of SARS-CoV-2 infection doubled every 1.56 days (95% CI 1.29-1.96) in barracks-style buildings. The corresponding doubling time for apartment-style buildings was 2.65 days (95% CI 2.01-3.87). CONCLUSIONS: Geospatial epidemiology was useful in shaping outbreak management strategies in dormitories. Our results indicate that building design plays an integral role in transmission and should be considered in the prevention of future outbreaks.

Current Status of Bruton's Tyrosine Kinase Inhibitor Development and Use in B-Cell Malignancies.

The B-cell receptor (BCR) pathway plays an important role in the survival, proliferation and trafficking of cancer cells in a variety of B-cell malignancies. Recently, a number of agents have been developed to target various components of the BCR pathway. One such target is Bruton's tyrosine kinase (BTK), a Tec family kinase member found near the cell membrane that is involved in upstream BCR signaling. The biological function of BTK in several B-cell lymphoid malignancies has led to the development of the oral BTK inhibitor ibrutinib. In chronic lymphocytic leukemia (CLL), ibrutinib has demonstrated durable clinical responses in relapsed/refractory (R/R) patients, including those with the high-risk del(17p) cytogenetic abnormality. These findings have paved the way for trials evaluating ibrutinib in previously untreated CLL patients, and also in combination with chemoimmunotherapy or other novel agents. Durable clinical responses have also been demonstrated in mantle cell lymphoma (MCL) and Waldenström's macroglobulinemia (WM) patients treated with ibrutinib. Ibrutinib is generally well tolerated, although current follow-up remains short and patients of advanced age are more likely to discontinue treatment for toxicity. Treatment-specific side effects such as bleeding and atrial fibrillation may, at least partly, be related to off-target inhibition of non-BTK kinases. Studies evaluating other potential indications for BTK inhibition are ongoing, including in post-allogeneic hematopoietic stem cell transplant patients for whom ibrutinib may be effective in modulating graft-versus-host disease. Combination trials of ibrutinib with venetoclax, a Bcl-2 inhibitor, are underway and are supported by sound preclinical rationale. Several next-generation BTK inhibitors are under development with the goal of decreasing treatment-related toxicity and resistance.

The potential combination of BCL-2 inhibitors and ibrutinib as frontline therapy in chronic lymphocytic leukemia.

The recent development of small molecule inhibitors targeted at the B-cell receptor (BCR) pathway and the anti-apoptotic protein BCL-2 has revolutionized the care of patients with chronic lymphocytic leukemia (CLL). While durable responses to the BCR inhibitor ibrutinib have been observed in both previously untreated and relapsed/refractory CLL patients, residual disease is common in patients treated with single-agent ibrutinib. Interest remains high in therapeutic combinations that may lead to better quality remissions. A potential partner to ibrutinib with a distinct mechanism of action that is likely to lead to deeper responses is the BCL-2 inhibitor venetoclax. Preclinical studies have suggested synergism between inhibitors of BCR and BCL-2 and have paved the way to the development of ongoing clinical trials aimed at evaluating the combination of ibrutinib with venetoclax in CLL patients.

A case that illustrates the challenges of managing pregnant patients with antithrombin deficiency: More questions than answers.

Using an illustrative case of a patient with antithrombin (AT) deficiency who developed a recurrent venous thromboembolism (VTE) in pregnancy despite therapeutic low-molecular-weight heparin (LMWH), we highlight what is known in the literature and address areas of controversy through a series of questions around the case. The questions we address include the role of anti-Xa monitoring for patients with past VTE on antepartum LMWH, what treatment regimen is recommended for pregnant patients who develop a recurrent VTE while on therapeutic anticoagulation, the role of antepartum AT concentrate prophylaxis, and the management of labor/delivery, epidural anesthesia and postpartum anticoagulation. We also describe practical considerations for use of AT concentrate, including teaching our patient to self-infuse AT concentrate at home with support of a hemophilia treatment center (HTC), and the direct and indirect costs of AT concentrate for secondary prophylaxis.

Survival of Del17p CLL Depends on Genomic Complexity and Somatic Mutation.

PURPOSE: Chronic lymphocytic leukemia (CLL) with 17p deletion typically progresses quickly and is refractory to most conventional therapies. However, some del(17p) patients do not progress for years, suggesting that del(17p) is not the only driving event in CLL progression. We hypothesize that other concomitant genetic abnormalities underlie the clinical heterogeneity of del(17p) CLL. EXPERIMENTAL DESIGN: We profiled the somatic mutations and copy number alterations (CNA) in a large group of del(17p) CLLs as well as wild-type CLL and analyzed the genetic basis of their clinical heterogeneity. RESULTS: We found that increased somatic mutation number associates with poor overall survival independent of 17p deletion (P = 0.003). TP53 mutation was present in 81% of del(17p) CLL, mostly clonal (82%), and clonal mutations with del(17p) exhibit shorter overall survival than subclonal mutations with del(17p) (P = 0.019). Del(17p) CLL has a unique driver mutation profile, including NOTCH1 (15%), RPS15 (12%), DDX3X (8%), and GPS2 (6%). We found that about half of del(17p) CLL cases have recurrent deletions at 3p, 4p, or 9p and that any of these deletions significantly predicts shorter overall survival. In addition, the number of CNAs, but not somatic mutations, predicts shorter time to treatment among patients untreated at sampling. Indolent del(17p) CLLs were characterized by absent or subclonal TP53 mutation and few CNAs, with no difference in somatic mutation number. CONCLUSIONS: We conclude that del(17p) has a unique genomic profile and that clonal TP53 mutations, 3p, 4p, or 9p deletions, and genomic complexity are associated with shorter overall survival. Clin Cancer Res; 23(3); 735-45. ©2016 AACR.

Effects of expectancy and abstinence on the neural response to smoking cues in cigarette smokers: an fMRI study.

Cues associated with drug taking can trigger relapse, drug seeking, and craving in addicted individuals. Behavioral studies suggest that drug availability and withdrawal can affect the individual response to drug cues. Moreover, the importance of subjective craving in cue-induced relapse has been questioned and an alternative model put forward according to which drug cues trigger habitual drug-seeking behaviors independently of craving. We used functional magnetic resonance imaging to compare the brain response to smoking and control videotapes in 20 healthy smokers, while varying their expectancy to smoke and abstinence levels. The neural response to cigarette cues was strongly modulated by expectancy and, to a lesser extent, abstinence. In people expecting to smoke immediately after the scan, smoking cues activated brain areas implicated in arousal, attention, and cognitive control. However, when subjects knew they would not be allowed to smoke for 4 h, there was almost no brain activation in response to smoking cues, despite equivalent reported levels of craving. In the dorsolateral prefrontal cortex, the neural response was a function of both craving and expectancy. Thalamo-cingulate connectivity, thought to be an index of arousal, was greater during expectancy than nonexpectancy. Our findings confirm the importance of expectancy in the neural response to drug cues, and lend support to the theory that these cues act on brain areas involved in arousal and attention.

Pax9 is required for filiform papilla development and suppresses skin-specific differentiation of the mammalian tongue epithelium.

The epidermis is a derivative of the surface ectoderm. It forms a protective barrier and specific appendages including hair, nails, and different eccrine glands. The surface ectoderm also forms the epithelium of the oral cavity and tongue, which develop a slightly different barrier and form different appendages such as teeth, filiform papillae, taste papillae, and salivary glands. How this region-specific differentiation is genetically controlled is largely unknown. We show here that Pax9, which is expressed in the epithelium of the tongue but not in skin, regulates several aspects of tongue-specific epithelial differentiation. In Pax9-deficient mice filiform papillae lack the anterior-posterior polarity, a defect that is associated with temporal-spatial changes in Hoxc13 expression. Barrier formation is disturbed in the mutant tongue and genome-wide expression profiling revealed that the expression of specific keratins (Krt), keratin-associated proteins, and members of the epidermal differentiation complex is significantly down-regulated. In situ hybridization demonstrated that several 'hard' keratins, Krt1-5, Krt1-24, and Krt2-16, are not expressed in the absence of Pax9. Notably, specific 'soft' keratins, Krt2-1 and Krt2-17, normally weakly expressed in the tongue but present at high levels in skin and in orthokeratinized oral dysplasia are up-regulated in the mutant tongue epithelium. This result indicates a partial trans-differentiation to an epithelium with skin-specific characteristics. Together, our findings show that Pax9 regulates appendage formation in the mammalian tongue and identify Pax9 as an important factor for the region-specific differentiation of the surface ectoderm.

Appropriateness of orthodontic referrals: self-perceived and normative treatment needs of patients referred for orthodontic consultation.

OBJECTIVES: The aims of this prospective study were to evaluate the self-perceived and normative orthodontic treatment needs of children referred for orthodontic consultation and to determine the proportion of children who were inappropriately referred. METHODS: The sample consisted of 257 children with a mean age of 12.0 years (SD = 2.4). An orthodontist assessed the children's normative treatment need using the dental health component (DHC) of the index of orthodontic treatment need (IOTN), and for patients in the mixed dentition the need for interceptive treatment was assessed. Questionnaires were answered by both the child and the parent to assess satisfaction with dental appearance and desire for treatment. RESULTS: The distribution of the IOTN grades showed that 73% of the children had definite need while 27% had borderline/no need for orthodontic treatment. Twenty-six per cent of children and 17% of parents did not express orthodontic concern, even though more than half of these children were in definite need of treatment as assessed by IOTN. The children's orthodontic concern was significantly related to the DHC scores. Out of the 103 children who were in the mixed dentition, only about 16% required interceptive treatment. CONCLUSIONS: The results indicated that a significant number of children were inappropriately referred for orthodontic treatment. Referring dentists need to assess the normative treatment needs of the children as well as the children's and parents' commitment and desire for orthodontic treatment before deciding on the need for referral.