Keeping a balance in chronic lymphocytic leukemia (CLL) patients taking ibrutinib: ibrutinib-associated adverse events and their management based on drug interactions
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Introduction Ibrutinib is a highly effective drug for patients with chronic lymphocytic leukemia (CLL), and is well tolerated even by older patients and those unfit to receive conventional immuno-chemotherapy.Areas covered The occurrence of adverse events was revealed as a major cause of ibrutinib failure in the real-world. Ibrutinib-induced lymphocytosis carries the risk of an untimely interruption of therapy because it may be misinterpreted as disease progression. In addition, drug interactions can worsen ibrutinib-associated toxicities by increasing the plasma concentration of ibrutinib. In this review, we present a case of major hemorrhage and atrial fibrillation (AF) during ibrutinib use and summarize the adverse events associated with ibrutinib. Furthermore, the practical management of ibrutinib-associated toxicities was covered with reference to a drug interaction mechanism.Expert opinion Clinicians should examine the prescribed drugs prior to ibrutinib initiation and carefully monitor toxicities while taking ibrutinib. A reduced dose of ibrutinib with the concurrent use of CYP3A inhibitors such as antifungal agents could be an attractive strategy to reduce toxicities and may confer financial benefits. Reducing unexpected toxicities is as significant as achieving treatment response in the era of life-long therapy with ibrutinib in patients with CLL.Cite
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Abstract Ibrutinib is approved for chronic lymphocytic leukemia (CLL). However, its role in the treatment of multiple myeloma (MM) is not clear and is under investigation. We report a case of CLL that developed MM while on therapy with ibrutinib indicating that this drug may not be active against MM.
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Results of RESONATE-2 (PCYC-1115/1116) supported approval of ibrutinib for first-line treatment of chronic lymphocytic leukemia. Extended analysis of RESONATE-2 was conducted to determine long-term efficacy and safety of ibrutinib in older patients with chronic lymphocytic leukemia. A total of 269 patients aged ≥65 years with previously untreated chronic lymphocytic leukemia without del(17p) were randomized 1:1 to ibrutinib (n=136) or chlorambucil (n=133) on days 1 and 15 of a 28-day cycle for 12 cycles. Median ibrutinib treatment duration was 28.5 months. Ibrutinib significantly prolonged progression-free survival versus chlorambucil (median, not reached vs. 15 months; hazard ratio, 0.12; 95% confidence interval, 0.07-0.20; P
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Chronic Lymphocytic Leukemia: Chronic Lymphocytic LeukemiaAbout one-third of patients with advanced chronic lymphocytic leukemia (CLL) treated with the targeted drug ibrutinib do not carry two mutated genes commonly associated with relapse, according to an international study published in Blood Advances (2023; https://doi.org/10.1182/bloodadvances.2022008821). The results were surprising since several previous studies identified BTK and/or less frequent mutations of the PLCG2 gene in the majority—up to 100 percent—of patients with CLL relapsing on ibrutinib, a therapy that has greatly improved patient outcomes for this disease. Instead, the study identified other mutations or pathways that may be teaming up to promote tumor progression and resistance to ibrutinib, potentially shedding light on new treatment options for these patients. “Patients with CLL progressing on ibrutinib are a new unmet need,” said Lydia Scarfò, MD, a physician-scientist at the Università Vita Salute San Raffaele in Milan, Italy, and co-investigator of this study coordinated by the European Research Initiative on CLL (ERIC). “Our work suggests that, besides BTK/PLCG2 mutations, additional mechanisms may contribute to the resistance and may be worth investigating as potential novel therapeutic targets in clinical trials.” Some patients with CLL die within several years of diagnosis, often due to complications from the disease, but many others may have a life expectancy similar to an age-matched healthy population. Ibrutinib is an oral inhibitor that targets Bruton tyrosine kinase (BTK), which plays a major role in B-cell malignancies including mantle cell lymphoma and CLL. The treatment has yielded high rates of durable response among particularly high-risk groups of patients for whom chemo-immunotherapy previously offered limited efficacy. Following three large clinical trials, ibrutinib was approved by the FDA in February 2014 and established as the treatment standard for CLL and small lymphocytic lymphoma. Even with this regimen that some say “revolutionized” treatment for these patients, about 6 percent of CLL patients develop resistance to and/or relapse within 6-12 months following initial therapy with another 14 percent doing so within 2 years. “Understanding these mechanisms and developing effective and safe methods to circumvent the emergence of resistance will determine the longer-term utility of these agents to improve patients' quality and length of life,” the researchers wrote in their article. “Rational drug combinations, optimized scheduling, and sequencing of therapy will likely hold the key to achieving these important goals.” Toward this end, the research team, under the leadership of Paolo Ghia, MD, PhD, Professor of Medical Oncology at the Università Vita-Salute San Raffaele in Italy and President of ERIC, searched for the presence of gene mutations from a panel of 252 genes relevant in lymphoid malignancies. Their efforts included a next-generation sequencing (NGS) approach called targeted deep sequencing in patients no longer responding to ibrutinib and a cohort of patients who continued to respond and remained on ibrutinib for at least 1 year after therapy was initiated. As outlined in their article, some 98 CLL patients treated with ibrutinib from 21 institutions were included in their study and assigned to one of two groups: relapsed (49 patients progressing after initial response) and responders (49 patients who maintained response to ibrutinib for 1 year or greater). Patients in both groups received ibrutinib without interruption for 15 days or greater. In all, some 151 blood and bone marrow samples and one paraffin-embedded lymph node sample were analyzed when treatment began 1 year or greater following the first day of therapy. Mutations that occurred more frequently in tumor samples, or hotspots, were validated through droplet digital polymerase chain reaction (ddPCR). By combining NGS and ddPCR results, some 32 of 49 relapsing cases—or 65 percent of the samples—carried at least one hotspot for BTK mutation and/or PLCG2 mutations. “This prevalence of BTK/PLCG2 mutations is lower than those reported in most previous studies,” the researchers wrote, “where the overall frequency of BTK and/or PLCG2 mutated relapse patients was up to 100 percent, hence indicating the existence of alternative mechanisms of resistance.” Further analysis revealed that other mechanisms, particularly BIRC3 and NFKBIE mutations, were found in cases without BTK mutations. “Both genes belong to the NF-κB pathway, pointing to an aberrant activation of this pathway as a potential mechanism leading to earlier progression and drug escape, even with the use of novel targeted agents,” Scarfò said. She cautioned that, in most cases, the team could analyze only peripheral blood samples, suggesting that some mutations in bone marrow and lymph nodes might have been missed or under-represented in their cohort. However, Scarfò added that the study provided “real-world evidence that is applicable to the patient population we encounter in the everyday clinical practice, completing data from clinical trials.” In the future, she said the study's results may spur clinical trials that exploit “biomarker-guided treatment strategies with novel inhibitors targeting differential signaling pathways based on” previously unidentified mutations. Warren Froelich is a contributing writer. Discover more research and news on chronic lymphocytic leukemia treatments in our online leukemia collection. Go to https://bit.ly/3LJcPNf and read articles on new clinical trials, combination therapies, and more.
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"Accelerated" chronic lymphocytic leukemia/small lymphocytic lymphoma (A-CLL) is a rare histological variant of CLL/SLL, which tends to exhibit an aggressive clinical behavior compared to CLL. Due to the rarity of A-CLL (<1% of all cases), the optimal management remains ill-defined. We report two cases of A-CLL from our institution, in which both relapsed following initial chemoimmunotherapy regimens. Both patients were treated with single agent ibrutinib, a Bruton's tyrosine kinase inhibitor (BTKi), and achieved rapid, deep and durable responses. With the absence of clear guidance on A-CLL treatment, BTKi agents should be considered in the frontline treatment of A-CLL.
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The clinical success of agents targeting the B-cell receptor signaling pathway in chronic lymphocytic leukemia (CLL) may also derive from disrupting the CLL microenvironment. Investigation of the immunomodulatory effects of these agents illuminates the unique immunobiology of CLL and highlights potential targets for dismantling the chronic inflammatory drive. See related article by Niemann et al., p. 1572.
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