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FISH cytogenetics, TP53 sequencing, and IGHV mutational status are increasingly used as prognostic and predictive markers in chronic lymphocytic leukemia (CLL), particularly as components of the CLL International Prognostic Index (CLL-IPI) and in directing therapy with novel agents. However, testing outside of clinical trials is not routinely available in Canada. As a centralized CLL clinic at CancerCare Manitoba, we are the first Canadian province to evaluate clinical outcomes and survivorship over a long period of time, incorporating the impact of molecular testing and the CLL-IPI score. We performed a retrospective analysis on 1315 patients diagnosed between 1960 and 2018, followed over a 12-year period, where 411 patients had molecular testing and 233 patients had a known CLL-IPI score at the time of treatment. Overall, 40.3% ( n = 530) of patients received treatment, and 47.5% ( n = 252) of patients received multiple lines of therapy. High-risk FISH and CLL-IPI (4-10) were associated with higher mortality (HR 2.03, p = 0.001; HR 2.64, p = 0.002), consistent with other studies. Over time, there was an increase in the use of targeted agents in treated patients. The use of Bruton's tyrosine kinase inhibitors improved survival in patients with unmutated IGHV and/or TP53 aberrations (HR 2.20, p = 0.001). The major cause of death in patients who received treatment was treatment/disease-related (32%, n = 42) and secondary malignancies (57%, n = 53) in those who were treatment-naïve. Our data demonstrate the importance of molecular testing in determining survivorship in CLL and underpinning the likely immune differences in outcomes for those treated for CLL.

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., Competing Interests: J.L. is a partner at PeriPharm Inc., a company that has served as a consultant to AbbVie and has received funding from AbbVie. J.L. and K.G. from PeriPharm Inc., have participated in the study conduct, data interpretation and the preparation of the manuscript. A.A has received honoraria from Abbvie and Astra Zeneca accepted into a separate account within the Ottawa Hospital Research Institute, for research/academic use only. V.B. has received research funding from CIHR, CancerCare Manitoba, Research Manitoba, Janssen and Abbvie and has served as a consultant to Abbvie, Janssen AstraZeneca, Gilead, Roche, and Lundbeck. I.F. has provided advisory consultations for Abbvie, AstraZeneca, BMS, Gilead, Janssen, Merck, Novartis, Roche and Seattle Genetics and has given presentations for Abbvie, Janssen, Novartis, Roche. C.O. has received honoraria from AbbVie, Astrazeneca, Janssen, Roche, Merck, Servier, Incyte. No author has received funding for developing the manuscript. AbbVie participated in the design and provided financial support for the study. AbbVie reviewed and approved this publication.

From a Canadian perspective, there has been a limited discussion on the frontline management of young, fit patients with chronic lymphocytic leukemia (CLL). The prevalence of this population ranges between 2 and 22 per 100,000 persons in Canada and varies by region. Until recently, fixed-duration fludarabine-based chemoimmunotherapy (CIT) was the primary treatment option in Canada for this patient population. The ECOG1912 trial has since demonstrated that ibrutinib and rituximab therapy are as effective as fludarabine-cyclophosphamide-rituximab (FCR) in this population. The ALLIANCE trial showed that rituximab added no incremental benefit to ibrutinib. Canadian payors and physicians adopted ibrutinib monotherapy as the CLL standard of care, even in the young, fit population, although frontline ibrutinib therapy is often reimbursed by provincial public drug plans only in patients with high-risk disease or those who are unfit to receive fludarabine. Young, fit patients with CLL and their physicians may now choose between continuous ibrutinib monotherapy and fixed-duration CIT with FCR. Factors affecting this choice include patient preference and the short- and long-term toxicity profiles of both regimens, and a risk-based algorithm is provided. As new continuous-therapy options enter the market, all treatment choices present benefits and risks that must be communicated to the patient.

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.

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., Competing Interests: CONFLICT OF INTEREST DISCLOSURES We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare the following interests: AC and SD received funding from AstraZeneca for the development of this paper. LHS has received honoraria from Hoffmann–La Roche/Genentech, AbbVie, Amgen, Apobiologix, AstraZeneca, Celgene, Gilead, Janssen, Kite, Karyopharm, Lundbeck, Merck, MorphoSys, Seattle Genetics, Teva, Takeda, and Verastem. VB has participated in advisory boards or received research funding from AstraZeneca, AbbVie, Janssen, Roche, Gilead, and Teva. She has received research funding from the Canadian Institutes of Health Research, the Leukemia and Lymphoma Society of Canada, the CancerCare Manitoba Foundation, and Research Manitoba. She receives licencing fees from Biogen for drugs unrelated to this manuscript. AA’s institution has received honoraria from AbbVie, AstraZeneca, Janssen, and Gilead. SR has received an honorarium from Hoffmann–La Roche/Genentech and has participated in advisory boards with AbbVie, Amgen, AstraZeneca, Celgene, Hoffmann–La Roche/Genentech, Janssen, Lundbeck, and Seattle Genetics., (2020 Multimed Inc.)

Chronic lymphocytic leukemia (cll) is the most common adult leukemia in the Western world. Unfortunately, affected patients are often immunosuppressed and at increased risk of infection and secondary malignancy. Previous meta-analysis has found that patients with cll have a risk of melanoma that is increased by a factor of 4 compared with the general population. Recent advances in the understanding of the PD receptor pathway have led to immunotherapies that target cancer cells. The use of PD-1 inhibitors is now considered first-line treatment for BRAF wild-type metastatic melanoma. Interestingly, early preclinical data suggest that inhibition of that pathway could also be used in the treatment of cll; however, recent clinical data did not support the effectiveness of that approach. In this case series, we highlight 2 cases in which patients with cll and concurrent malignant melanoma underwent treatment with PD-1 inhibitors and were found to experience reductions in their white blood cell counts without improvement in their hemoglobin. Those cases further illustrate that treatment of cll with PD-1 inhibitors is ineffective., Competing Interests: CONFLICT OF INTEREST DISCLOSURES We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare that we have none., (2020 Multimed Inc.)

Background: Ibrutinib is an approved treatment for relapsed or refractory chronic lymphocytic leukemia (cll) and small lymphocytic lymphoma (sll). The effect of ibrutinib dose reduction compared with discontinuation in a population-based setting is unclear., Methods: To examine the patterns of ibrutinib use in a Canadian population-based setting, we analyzed a retrospective cohort of patients with relapsed or refractory cll or sll treated with ibrutinib., Results: The 64 patients diagnosed with cll or sll had a median age of 76.5 years. Most had unmutated ighv (immunoglobulin variable heavy chain). A hematologic response occurred in 39 patients regardless of the ibrutinib dose. The most common toxicities were infection, bruising or bleeding, and musculoskeletal problems, with a median time to first toxicity of 14 days. More than half the cohort experienced a dose reduction, with musculoskeletal problems, cytopenias, and infection being the leading causes; surgery was the most frequent indication for holding treatment. Only 26 of the 64 patients (40.6%) stayed on the recommended maximal dose of ibrutinib. No differences in reported toxicities or hematologic response rates were evident between the patients receiving maximal and submaximal therapy. At the end of the study period, 53 patients from the initial cohort remained on ibrutinib., Conclusions: More than half the study patients received ibrutinib therapy at a submaximal dose without evidence of increased frequency of toxicities or disease progression. The rate of ibrutinib discontinuation was lower in our cohort than has been reported in other settings. Submaximal ibrutinib dosing will have to be further systematically evaluated., Competing Interests: CONFLICT OF INTEREST DISCLOSURES We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare the following interests: DD has attended advisory boards for AstraZeneca and Merck, and has received an honorarium from Boehringer Ingelheim; VB has attended advisory boards for Janssen, AbbVie, and Astra Zeneca; VB and JBJ have received research funding from Janssen and Gilead; and VB has received research funding from Research Manitoba CLLuster, a New investigator Grant, and the CancerCare Manitoba Foundation. The remaining authors have no conflicts of interest to disclose., (2019 Multimed Inc.)

Nontraumatic chylous pleural effusions (chylothorax) and pericardial effusions (chylopericardium) are rare. They can, however, accompany intrathoracic malignancies and, most commonly, lymphomas. An association of chronic lymphocytic leukemia (cll) with chylopericardium has rarely been reported. A 68-year-old woman with cll, previously treated with single-agent fludarabine in the community, developed pleuritic chest pain and a new pericardial effusion. Computed tomography (ct) imaging of her chest revealed a large pericardial effusion with progressive lymphadenopathy. Pericardiocentesis identified a chylous effusion, and complete evacuation was achieved by catheter drainage. The cll was not treated. An asymptomatic pericardial effusion subsequently recurred. Pericardiocentesis was not repeated. Lymph node biopsy and flow cytometry revealed no evidence of large-cell lymphoma transformation. The patient was treated with 6 cycles of chlorambucil and obinutuzumab. Imaging of her chest by ct between cycles 2 and 3 revealed a marked resolution of the intrathoracic lymphadenopathy, with complete disappearance of the pericardial effusion. Repeat imaging at 5 months and again at 3 years after completion of chemotherapy demonstrated no recurrence of either the lymphadenopathy or the pericardial effusion. The mechanism of production and the treatment of chylous effusions are poorly defined. In this case, resolution of the pericardial effusion with effective chemotherapy is postulated to have alleviated obstruction of anterograde lymphatic flow facilitating drainage into the systemic venous system and allowing for spontaneous complete resolution of the pericardial effusion without surgical intervention., Competing Interests: CONFLICT OF INTEREST DISCLOSURES We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare that we have none., (2019 Multimed Inc.)

Chronic lymphocytic leukemia (cll) is the most common adult leukemia in North America. In Canada, no unified national guideline exists for the front-line treatment of cll; provincial guidelines vary and are largely based on funding. A group of clinical experts from across Canada developed a national evidence-based treatment guideline to provide health care professionals with clear guidance on the first-line management of cll. Consensus recommendations based on available evidence are presented for the first-line treatment of cll., Competing Interests: CONFLICT OF INTEREST DISCLOSURES We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare the following interests: CO reports personal fees from Roche, Janssen, Gilead, AbbVie, Merck, AstraZeneca, and Lundbeck/Teva outside the submitted work; VB sits on advisory boards for AstraZeneca, AbbVie, Janssen, Lundbeck, Gilead, Roche, and has received grants from Research Manitoba, the CancerCare Manitoba Foundation, and Lundbeck outside the submitted work; ASG reports personal fees from Janssen, Lundbeck, and AbbVie outside the submitted work; SA reports personal fees from Roche and Pfizer outside the submitted work; CC reports other considerations from Celgene, Janssen, and Gilead outside the submitted work; KSR reports personal fees from Celgene, Janssen, Gilead, Roche, AstraZeneca, and AbbVie outside the submitted work; EL reports grants from Roche, Gilead, and Lundbeck during the conduct of the study; GF reports grants and personal fees from Celgene and AbbVie, and personal fees from Janssen outside the submitted work.