Sequencing and combination of current small-molecule inhibitors for chronic lymphocytic leukemia: Where is the evidence?

Small-molecule inhibitors have revolutionized the treatment of chronic lymphocytic leukemia (CLL), a landscape once dominated by chemoimmunotherapy (i.e., an anti-CD20 monoclonal antibody in combination with systemic chemotherapy) in fit and unfit individuals. Key challenges include the management of refractory disease as well as the optimization of the therapy sequence. Decreased responsiveness has been observed with prolonged treatment, especially with Bruton tyrosine kinase (BTK) and phosphatidylinositol 3-kinase (PI3K) inhibitors which are given continuously, while venetoclax, an agent that targets dysregulations in intrinsic apoptosis signaling, has a fixed duration when combined with anti-CD20 monoclonal antibodies or BTK inhibitors. Combination therapy aims to synergistically target different oncogenic signaling pathways to abrogate the proliferation of resistant clones and thereby allows for fixed-duration treatments. An advantage of fixed-duration therapy is the potential to decrease financial and drug-induced toxicities. Sequencing of therapies is important to individualize treatment decisions based on factors such as age, comorbidities, tolerability, and patient preferences. However, to date, there are limited data to guide the rational sequencing or combination of these therapies, since conventional chemoimmunotherapy or chemotherapy regimens were used as comparators against these small-molecule inhibitors in trials that led to their regulatory approvals. In this article, we examined and evaluated the current evidence for sequencing versus the combination of small-molecule inhibitors for CLL by conducting comprehensive searches of the United States National Library of Medicine PubMed database, key meeting abstracts, and clinical practice guidelines. We also summarized findings from expert opinions to elucidate best practices for clinical scenarios with limited evidence to guide treatment selection.

Incidence of chemotherapy-induced peripheral neuropathy within 12 weeks of starting neurotoxic chemotherapy for multiple myeloma or lymphoma: a prospective, single-center, observational study.

PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) may necessitate chemotherapy dose reduction, delay, or discontinuation. This pilot study tested feasibility of patient enrollment, CIPN screening, and data collection in cancer patients for a future clinical study that will assess the safety and efficacy of an intervention that may prevent CIPN. METHODS: This prospective, observational, single-center, pilot study included adults with newly diagnosed lymphoma or multiple myeloma receiving neurotoxic chemotherapy. Patients were enrolled between September 2016 and February 2017. The Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) questionnaire was completed by patients at 3 time points: baseline, week 6, and week 12. The primary outcome was change in the neurotoxicity score between these time points. RESULTS: Of 33 patients approached for consent, 28 (85%) provided consent and were enrolled. The FACT/GOG-Ntx questionnaire was completed by 28 (100%) at baseline, 25 (89%) at week 6, and 24 (86%) at week 12. Average (standard deviation) neurotoxicity scores were 36.5 (6.6) at baseline, 34.0 (8.3) at week 6, and 30.6 (7.6) at week 12. Neurotoxicity scores changed from baseline by - 2.7 points (95% CI - 5.5 to 0.1; p = 0.061) at week 6 and - 6.0 points (95% CI - 5.6 to - 0.8; p = 0.012) at week 12. Clinically meaningful declines (decrease of > 10% from baseline) in neurotoxicity score were detected in 36% (9 of 25) at week 6 and in 67% (16 of 24) at week 12. CONCLUSION: Sixty-seven percent of patients experienced clinically significant CIPN within 12 weeks of starting chemotherapy. Feasibility metrics for enrollment, consent, CIPN assessment, and follow-up were met.

Single-center, retrospective evaluation of safety and efficacy of direct oral anticoagulants versus low-molecular-weight heparin and vitamin K antagonist in patients with cancer.

INTRODUCTION: The safety and efficacy of direct oral anticoagulants in cancer patients is currently unclear. Low-molecular-weight heparin remains the standard of care for cancer patients with venous thromboembolism, with warfarin, a vitamin K antagonist, as an alternative. Clear recommendations do not exist for patients with both active cancer and non-valvular atrial fibrillation. The objectives of this study were to report safety and efficacy outcomes of direct oral anticoagulants, low-molecular-weight heparin, and vitamin K antagonist in cancer patients with venous thromboembolism or non-valvular atrial fibrillation. METHODS: Retrospective chart review of adult cancer patients from 2012 to 2015 who received an antineoplastic agent and an anticoagulant. RESULTS: A total of 258 patients were reviewed: 80 patients in direct oral anticoagulant group, 95 patients in low-molecular-weight heparin group, and 83 patients in vitamin K antagonist group. Sixty-seven percent of patients were on an anticoagulant for acute or chronic venous thromboembolism. Major bleeding events were similar across the groups (15% direct oral anticoagulant vs 17% low-molecular-weight heparin vs 18% vitamin K antagonist). The most common type of major bleeding event was gastrointestinal bleeding. A total of five fatal bleeding events occurred. Venous thromboembolism recurrence rates were higher in both direct oral anticoagulant (18%) and low-molecular-weight heparin (12%) groups while lower in vitamin K antagonist group (10%) compared to previous studies. CONCLUSIONS: Cancer patients receiving direct oral anticoagulants, low-molecular-weight heparin, or vitamin K antagonist had similar rates of major bleeding events, with gastrointestinal bleeding being the most common event. Venous thromboembolism recurrence rates were higher in direct oral anticoagulant and low-molecular-weight heparin groups than prior studies. Randomized trials are warranted to establish clear safety and efficacy in this population.