Ibrutinib for chronic lymphocytic leukemia: international experience from a named patient program.
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ABSTRACT:
SUBMITTER: Hillmen P
PROVIDER: S-EPMC5927988 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:B-cell receptor (BCR) signaling is essential for chronic lymphocytic leukemia (CLL) cell survival. Many kinases in the BCR signaling pathway are being studied as potential therapeutic targets. Ibrutinib (PCI-32765) is a novel first-in-class selective inhibitor of Bruton tyrosine kinase. Preclinical evidence suggests that ibrutinib inhibits CLL cell survival and proliferation and affects CLL cell migration and homing. Early clinical data in patients with CLL and non-Hodgkin lymphoma is encouraging. It is likely that ibrutinib and other drugs targeting the BCR pathway will become an integral component of CLL therapy.
| S-EPMC4449150 | biostudies-other
Project description:Ibrutinib is the first in-class, orally administered, Bruton's tyrosine kinase (BTK) inhibitor that abrogates the critical signaling downstream of the B-cell receptor (BCR). This signaling is required for B-cell survival, proliferation and interaction with the microenvironment. Ibrutinib proved active in preclinical models of lymphoproliferative diseases and achieved impressive response rates in heavily pretreated relapsed and refractory (R/R) patients with chronic lymphocytic leukemia (CLL). Ibrutinib prolonged survival compared to standard therapy and mitigated the effect of most poor prognostic factors in CLL, thus becoming the main therapeutic option in high-risk populations. Moreover, compared with standard chemoimmunotherapy (CIT) for adults, ibrutinib causes fewer cytopenias and infections, while having its own unique toxicity profile. Its efficacy in relapsed patients as well as its tolerability have led to its increased use in previously untreated patients, especially in those with poor prognostic markers and/or the elderly. This review elaborates on ibrutinib's unique toxicity profile and the mechanisms of acquired resistance leading to progression on ibrutinib, since both are critical for understanding the obstacles to its first-line use. We will further evaluate the data from ongoing clinical trials in this setting and explore future options for combination therapy.
| S-EPMC5753924 | biostudies-literature
Project description:Ibrutinib is the first Bruton's tyrosine kinase (BTK) inhibitor, which showed significant clinical activity in chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) patients regardless of cytogenetic risk factors. Recent results of phase III clinical trials in treatment-naïve CLL patients shift the importance of the agent to frontline therapy. Nevertheless, beside its clinical efficacy, ibrutinib possesses some off-target activity resulting in ibrutinib-characteristic adverse events including bleeding diathesis and arrhythmias. Furthermore, acquired and primary resistance to the drug have been described. As the use of ibrutinib in clinical practice increases, the problem of resistance is becoming apparent, and new methods of overcoming this clinical problem arise. In this review, we summarize the mechanisms of BTK inhibitors' resistance and discuss the post-ibrutinib treatment options.
| S-EPMC6966427 | biostudies-literature
Project description:COVID-19 is affecting many countries all around the world. Unfortunately, no treatment has already been approved for the management of patients infected by SARS-CoV-2. It seems that SARS-CoV-2 can induce the activation of an exaggerated immune response against itself according to different mechanisms that are not really well known. Inflammatory interleukins, such as IL-6 among others, play a central role in this uncontrolled immune response. There is a strong rational under ibrutinib use in in the treatment of immune-based diseases, such a as GVHD or RA. Ibrutinib achieves a reduction in the production of TNFα, IL1, IL-6 and Monocyte chemo-attractant protein-1 (MCP-1) by neutrophils and macrophages, that are key players in keeping the inflammatory process. We present our clinical experience about ibrutinib use in ARDS secondary to SARS-CoV-2 in a patient with chronic lymphocytic leukemia (CLL).
| S-EPMC7830068 | biostudies-literature
Project description:BackgroundData regarding the efficacy of treatment with ibrutinib-rituximab, as compared with standard chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab, in patients with previously untreated chronic lymphocytic leukemia (CLL) have been limited.MethodsIn a phase 3 trial, we randomly assigned (in a 2:1 ratio) patients 70 years of age or younger with previously untreated CLL to receive either ibrutinib and rituximab for six cycles (after a single cycle of ibrutinib alone), followed by ibrutinib until disease progression, or six cycles of chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab. The primary end point was progression-free survival, and overall survival was a secondary end point. We report the results of a planned interim analysis.ResultsA total of 529 patients underwent randomization (354 patients to the ibrutinib-rituximab group, and 175 to the chemoimmunotherapy group). At a median follow-up of 33.6 months, the results of the analysis of progression-free survival favored ibrutinib-rituximab over chemoimmunotherapy (89.4% vs. 72.9% at 3 years; hazard ratio for progression or death, 0.35; 95% confidence interval [CI], 0.22 to 0.56; P<0.001), and the results met the protocol-defined efficacy threshold for the interim analysis. The results of the analysis of overall survival also favored ibrutinib-rituximab over chemoimmunotherapy (98.8% vs. 91.5% at 3 years; hazard ratio for death, 0.17; 95% CI, 0.05 to 0.54; P<0.001). In a subgroup analysis involving patients without immunoglobulin heavy-chain variable region (IGHV) mutation, ibrutinib-rituximab resulted in better progression-free survival than chemoimmunotherapy (90.7% vs. 62.5% at 3 years; hazard ratio for progression or death, 0.26; 95% CI, 0.14 to 0.50). The 3-year progression-free survival among patients with IGHV mutation was 87.7% in the ibrutinib-rituximab group and 88.0% in the chemoimmunotherapy group (hazard ratio for progression or death, 0.44; 95% CI, 0.14 to 1.36). The incidence of adverse events of grade 3 or higher (regardless of attribution) was similar in the two groups (in 282 of 352 patients [80.1%] who received ibrutinib-rituximab and in 126 of 158 [79.7%] who received chemoimmunotherapy), whereas infectious complications of grade 3 or higher were less common with ibrutinib-rituximab than with chemoimmunotherapy (in 37 patients [10.5%] vs. 32 [20.3%], P<0.001).ConclusionsThe ibrutinib-rituximab regimen resulted in progression-free survival and overall survival that were superior to those with a standard chemoimmunotherapy regimen among patients 70 years of age or younger with previously untreated CLL. (Funded by the National Cancer Institute and Pharmacyclics; E1912 ClinicalTrials.gov number, NCT02048813.).
| S-EPMC6908306 | biostudies-literature
Project description:Ibrutinib (Imbruvica): a novel targeted therapy for chronic lymphocytic leukemia.
| S-EPMC4103574 | biostudies-other
Project description:Chronic lymphocytic leukemia (CLL) primarily affects older persons who often have coexisting conditions in addition to disease-related immunosuppression and myelosuppression. We conducted an international, open-label, randomized phase 3 trial to compare two oral agents, ibrutinib and chlorambucil, in previously untreated older patients with CLL or small lymphocytic lymphoma.We randomly assigned 269 previously untreated patients who were 65 years of age or older and had CLL or small lymphocytic lymphoma to receive ibrutinib or chlorambucil. The primary end point was progression-free survival as assessed by an independent review committee.The median age of the patients was 73 years. During a median follow-up period of 18.4 months, ibrutinib resulted in significantly longer progression-free survival than did chlorambucil (median, not reached vs. 18.9 months), with a risk of progression or death that was 84% lower with ibrutinib than that with chlorambucil (hazard ratio, 0.16; P<0.001). Ibrutinib significantly prolonged overall survival; the estimated survival rate at 24 months was 98% with ibrutinib versus 85% with chlorambucil, with a relative risk of death that was 84% lower in the ibrutinib group than in the chlorambucil group (hazard ratio, 0.16; P=0.001). The overall response rate was higher with ibrutinib than with chlorambucil (86% vs. 35%, P<0.001). The rates of sustained increases from baseline values in the hemoglobin and platelet levels were higher with ibrutinib. Adverse events of any grade that occurred in at least 20% of the patients receiving ibrutinib included diarrhea, fatigue, cough, and nausea; adverse events occurring in at least 20% of those receiving chlorambucil included nausea, fatigue, neutropenia, anemia, and vomiting. In the ibrutinib group, four patients had a grade 3 hemorrhage and one had a grade 4 hemorrhage. A total of 87% of the patients in the ibrutinib group are continuing to take ibrutinib.Ibrutinib was superior to chlorambucil in previously untreated patients with CLL or small lymphocytic lymphoma, as assessed by progression-free survival, overall survival, response rate, and improvement in hematologic variables. (Funded by Pharmacyclics and others; RESONATE-2 ClinicalTrials.gov number, NCT01722487.).
| S-EPMC4722809 | biostudies-other
Project description: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.
| S-EPMC7495781 | biostudies-literature
Project description:We previously reported durable responses and manageable safety of ibrutinib from a 3-year follow-up of treatment-naïve (TN) older patients (≥65 years of age) and relapsed/refractory (R/R) patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). We now report on long-term efficacy and safety with median follow-up of 5 years in this patient population with TN (N = 31) and R/R (N = 101) CLL/SLL. With the current 5-year follow-up, ibrutinib continues to yield a high overall response rate of 89%, with complete response rates increasing over time to 29% in TN patients and 10% in R/R patients. The median progression-free survival (PFS) was not reached in TN patients. The 5-year PFS rate was 92% in TN patients and 44% in R/R patients. Median PFS in R/R patients was 51 months; in those with del(11q), del(17p), and unmutated IGHV, it was 51, 26, and 43 months, respectively, demonstrating long-term efficacy of ibrutinib in some high-risk subgroups. Survival outcomes were less robust for R/R patients with del(17p) and those who received more prior therapies. The onset of grade ≥3 cytopenias, such as neutropenia and thrombocytopenia, decreased over time. Treatment--limiting adverse events were more frequent during the first year compared with subsequent periods. These results demonstrate sustained efficacy and acceptable tolerability of ibrutinib over an extended time, providing the longest experience for Bruton tyrosine kinase inhibitor treatment in patients with CLL/SLL. These trials were registered at www.clinicaltrials.gov as #NCT01105247 and #NCT01109069.
| S-EPMC5921964 | biostudies-literature
Project description:The Bruton tyrosine kinase inhibitor (BTKi) ibrutinib is a new targeted therapy for patients with chronic lymphocytic leukemia (CLL). Ibrutinib is given orally on a continuous schedule and induces durable remissions in the majority of CLL patients. However, a small proportion of patients initially responds to the BTKi and then develops resistance. Estimating the frequency, timing, and individual risk of developing resistance to ibrutinib, therefore, would be valuable for long-term management of patients. Computational evolutionary models, based on measured kinetic parameters of patients, allow us to approach these questions and to develop a roadmap for personalized prognosis and treatment management. Our kinetic models predict that BTKi-resistant mutants exist before initiation of ibrutinib therapy, although they only comprise a minority of the overall tumor burden. Furthermore, we can estimate the time required for resistant cells to grow to detectable levels. We predict that this can be highly variable, depending mostly on growth and death rates of the individual CLL cell clone. For a specific patient, this time can be predicted with a high degree of certainty. Our model can thus be used to predict for how long ibrutinib can suppress the disease in individual patients. Furthermore, the model can suggest whether prior debulking of the tumor with chemo-immunotherapy can prolong progression-free survival under ibrutinib. Finally, by applying the models to data that document progression during ibrutinib therapy, we estimated that resistant mutants might have a small (<2%) mean fitness advantage in the absence of treatment, compared with sensitive cells.
| S-EPMC4183279 | biostudies-literature