The Experts below are selected from a list of 3453 Experts worldwide ranked by ideXlab platform
Jos H. Beijnen - One of the best experts on this subject based on the ideXlab platform.
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p glycoprotein mdr1 abcb1 restricts brain penetration of the bruton s tyrosine kinase inhibitor Ibrutinib while cytochrome p450 3a cyp3a limits its oral bioavailability
Molecular Pharmaceutics, 2018Co-Authors: Stephanie Van Hoppe, Levi C M Buil, Els Wagenaar, Rolf W Sparidans, Johannes J M Rood, Jos H. BeijnenAbstract:Ibrutinib (Imbruvica), an oral tyrosine kinase inhibitor (TKI) approved for treatment of B-cell malignancies, irreversibly inhibits the Bruton’s tyrosine kinase (BTK). Its abundant metabolite, dihydrodiol-Ibrutinib (Ibrutinib-DiOH), which is primarily formed by CYP3A, has a 10-fold reduced BTK inhibitory activity. Using in vitro transport assays and genetically modified mouse models, we investigated whether the multidrug efflux transporters ABCB1 and ABCG2 and the multidrug-metabolizing CYP3A enzyme family can affect the oral bioavailability and tissue disposition of Ibrutinib and Ibrutinib-DiOH. In vitro, Ibrutinib was transported moderately by human ABCB1 and mouse Abcg2 but not detectably by human ABCG2. In mice, Abcb1 markedly restricted the brain penetration of Ibrutinib and Ibrutinib-DiOH, either alone or in combination with Abcg2, resulting in 4.5- and 5.9-fold increases in Ibrutinib brain-to-plasma ratios in Abcb1a/1b–/– and Abcb1a/1b;Abcg2–/– mice relative to wild-type mice. Abcb1 and/or Abcg2 di...
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p glycoprotein mdr1 abcb1 restricts brain penetration of the bruton s tyrosine kinase inhibitor Ibrutinib while cytochrome p450 3a cyp3a limits its oral bioavailability
Molecular Pharmaceutics, 2018Co-Authors: Stephanie Van Hoppe, Levi C M Buil, Els Wagenaar, Rolf W Sparidans, Johannes J M Rood, Jos H. Beijnen, Alfred H. SchinkelAbstract:Ibrutinib (Imbruvica), an oral tyrosine kinase inhibitor (TKI) approved for treatment of B-cell malignancies, irreversibly inhibits the Bruton's tyrosine kinase (BTK). Its abundant metabolite, dihydrodiol-Ibrutinib (Ibrutinib-DiOH), which is primarily formed by CYP3A, has a 10-fold reduced BTK inhibitory activity. Using in vitro transport assays and genetically modified mouse models, we investigated whether the multidrug efflux transporters ABCB1 and ABCG2 and the multidrug-metabolizing CYP3A enzyme family can affect the oral bioavailability and tissue disposition of Ibrutinib and Ibrutinib-DiOH. In vitro, Ibrutinib was transported moderately by human ABCB1 and mouse Abcg2 but not detectably by human ABCG2. In mice, Abcb1 markedly restricted the brain penetration of Ibrutinib and Ibrutinib-DiOH, either alone or in combination with Abcg2, resulting in 4.5- and 5.9-fold increases in Ibrutinib brain-to-plasma ratios in Abcb1a/1b-/- and Abcb1a/1b;Abcg2-/- mice relative to wild-type mice. Abcb1 and/or Abcg2 did not obviously restrict Ibrutinib oral bioavailability, but Cyp3a deficiency increased the Ibrutinib plasma AUC by 9.7-fold compared to wild-type mice. This increase was mostly reversed (5.1-fold reduction) by transgenic human CYP3A4 overexpression, with roughly equal contributions of intestinal and hepatic CYP3A4 metabolism. Our results suggest that pharmacological inhibition of ABCB1 during Ibrutinib therapy might benefit patients with malignancies or (micro)metastases positioned behind an intact blood-brain barrier, or with substantial expression of this transporter in the malignant cells. Moreover, given the strong in vivo impact of CYP3A, inhibitors or inducers of this enzyme family will likely strongly affect Ibrutinib oral bioavailability and, thus, its therapeutic efficacy, as well as its toxicity risks.
Jan A Burger - One of the best experts on this subject based on the ideXlab platform.
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long term efficacy and safety of first line Ibrutinib treatment for patients with cll sll 5 years of follow up from the phase 3 resonate 2 study
Leukemia, 2020Co-Authors: Jan A Burger, Steven Coutre, Alessandra Tedeschi, Paul M Barr, Tadeusz Robak, Carolyn Owen, Paolo Ghia, Osnat Bairey, Peter Hillmen, Stephen DevereuxAbstract:RESONATE-2 is a phase 3 study of first-line Ibrutinib versus chlorambucil in chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Patients aged ≥65 years (n = 269) were randomized 1:1 to once-daily Ibrutinib 420 mg continuously or chlorambucil 0.5-0.8 mg/kg for ≤12 cycles. With a median (range) follow-up of 60 months (0.1-66), progression-free survival (PFS) and overall survival (OS) benefits for Ibrutinib versus chlorambucil were sustained (PFS estimates at 5 years: 70% vs 12%; HR [95% CI]: 0.146 [0.098-0.218]; OS estimates at 5 years: 83% vs 68%; HR [95% CI]: 0.450 [0.266-0.761]). Ibrutinib benefit was also consistent in patients with high prognostic risk (TP53 mutation, 11q deletion, and/or unmutated IGHV) (PFS: HR [95% CI]: 0.083 [0.047-0.145]; OS: HR [95% CI]: 0.366 [0.181-0.736]). Investigator-assessed overall response rate was 92% with Ibrutinib (complete response, 30%; 11% at primary analysis). Common grade ≥3 adverse events (AEs) included neutropenia (13%), pneumonia (12%), hypertension (8%), anemia (7%), and hyponatremia (6%); occurrence of most events as well as discontinuations due to AEs decreased over time. Fifty-eight percent of patients continue to receive Ibrutinib. Single-agent Ibrutinib demonstrated sustained PFS and OS benefit versus chlorambucil and increased depth of response over time.
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single agent Ibrutinib versus chemoimmunotherapy regimens for treatment naive patients with chronic lymphocytic leukemia a cross trial comparison of phase 3 studies
American Journal of Hematology, 2018Co-Authors: Tadeusz Robak, Jan A Burger, Alessandra Tedeschi, Paul M Barr, Carolyn Owen, Osnat Bairey, Peter Hillmen, David Simpson, Sebastian Grosicki, Stephen DevereuxAbstract:Chemoimmunotherapy (CIT) and targeted therapy with single-agent Ibrutinib are both recommended first-line treatments for chronic lymphocytic leukemia (CLL), although their outcomes have not been directly compared. Using Ibrutinib data from the RESONATE-2 (PCYC-1115/1116) study conducted in patients ≥65 years without del(17p), we performed a cross-trial comparison with CIT data from published phase 3 studies in first-line treatment of CLL. Progression-free survival (PFS), overall survival (OS), and safety data for Ibrutinib (median follow-up 35.7 months) were evaluated alongside available CIT data. CIT regimens included: fludarabine + cyclophosphamide + rituximab (CLL8, CLL10), bendamustine + rituximab (CLL10), obinutuzumab + chlorambucil and rituximab + chlorambucil (CLL11), and ofatumumab + chlorambucil (COMPLEMENT-1). Median age across studies was 61-74 years, with older populations receiving Ibrutinib, obinutuzumab + chlorambucil, or rituximab + chlorambucil. Median follow-up varied across studies/regimens (range 14.5-37.4 months). Among all patients, PFS appeared longer with Ibrutinib relative to CIT and OS appeared comparable. Relative to CIT studies that similarly excluded patients with del(17p) (CLL10) or enrolled older/less-fit patients (CLL11), PFS appeared favorable for Ibrutinib in high-risk subgroups, including advanced disease, bulky lymph nodes, unmutated IGHV status, and presence of del(11q). Grade ≥ 3 infections ranged from 9% (ofatumumab + chlorambucil) to 40% (fludarabine + cyclophosphamide + rituximab), and was 25% with Ibrutinib. Grade ≥ 3 neutropenia was 12% for Ibrutinib and 26%-84% for CIT. Although definitive conclusions cannot be made due to inherent limitations of cross-trial comparisons, this report suggests that Ibrutinib has a favorable benefit/risk profile and may potentially eliminate the need for chemotherapy in some patients. Randomized, comparative studies are needed to support these findings.
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Ibrutinib modulates the immunosuppressive cll microenvironment through stat3 mediated suppression of regulatory b cell function and inhibition of the pd 1 pd l1 pathway
Leukemia, 2018Co-Authors: Kayo Kondo, Hila Shaim, Philip A Thompson, Jan A Burger, M Keating, Zeev Estrov, David Harris, Ekaterina Kim, Alessandra Ferrajoli, May DaherAbstract:Ibrutinib, a covalent inhibitor of Bruton Tyrosine Kinase (BTK), is approved for treatment of patients with relapsed/refractory or treatment-naive chronic lymphocytic leukemia (CLL). Besides directly inhibiting BTK, Ibrutinib possesses immunomodulatory properties through targeting multiple signaling pathways. Understanding how this ancillary property of Ibrutinib modifies the CLL microenvironment is crucial for further exploration of immune responses in this disease and devising future combination therapies. Here, we investigated the mechanisms underlying the immunomodulatory properties of Ibrutinib. In peripheral blood samples collected prospectively from CLL patients treated with Ibrutinib monotherapy, we observed selective and durable downregulation of PD-L1 on CLL cells by 3 months post-treatment. Further analysis showed that this effect was mediated through inhibition of the constitutively active signal transducer and activator of transcription 3 (STAT3) in CLL cells. Similar downregulation of PD-1 was observed in CD4+ and CD8+ T cells. We also demonstrated reduced interleukin (IL)-10 production by CLL cells in patients receiving Ibrutinib, which was also linked to suppression of STAT3 phosphorylation. Taken together, these findings provide a mechanistic basis for immunomodulation by Ibrutinib through inhibition of the STAT3 pathway, critical in inducing and sustaining tumor immune tolerance. The data also merit testing of combination treatments combining Ibrutinib with agents capable of augmenting its immunomodulatory effects.
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Ibrutinib fludarabine cyclophosphamide and obinutuzumab ga101 ifcg for previously untreated patients with chronic lymphocytic leukemia cll with mutated ighv and non del 17p
Journal of Clinical Oncology, 2017Co-Authors: Nitin Jain, Philip A Thompson, Jan A Burger, Zeev Estrov, Alessandra Ferrajoli, Gautam Borthakur, Prithviraj Bose, Varsha Gandhi, William Plunkett, Wanda LopezAbstract:7522Background: Pts with mutated IGHV (IGHV-M) have favorable long-term outcomes after FCR. Methods: We designed an investigator-initiated phase II trial with Ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) for previously untreated pts with IGHV-M CLL (NCT02629809). The intent was to limit FC to 3 courses, potentially reducing short- and long-term toxicity, while maintaining efficacy through addition of Ibrutinib and obinutuzumab. Key eligibility included age ≥18, IGHV-M, no del17p. Pts received 3 courses of iFCG. G-CSF was not mandated. Primary endpoint: CR/CRi with bone marrow (BM) MRD-neg (4-color flow-cytometry) after 3 courses of iFCG. Pts meeting primary endpoint received Ibrutinib with obinutuzumab (iG) for C3-6, then Ibrutinib C7-12. Pts not achieving primary endpoint received iG (C4-12). All pts who are MRD neg at 1 year will stop all therapy, including Ibrutinib. Pts MRD+ at 1 year may continue Ibrutinib. Historic C3 BM MRD-neg with FCR in IGHV-M 26% (Strati, Blood 2014). Targe...
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Ibrutinib modifies the function of monocyte macrophage population in chronic lymphocytic leukemia
Oncotarget, 2016Co-Authors: Stefania Fiorcari, Rossana Maffei, Valentina Audrito, Silvia Martinelli, Elisa Ten Hacken, Patrizia Zucchini, Giulia Grisendi, Leonardo Potenza, Mario Luppi, Jan A BurgerAbstract:// Stefania Fiorcari 1, * , Rossana Maffei 1, * , Valentina Audrito 2 , Silvia Martinelli 1 , Elisa ten Hacken 3 , Patrizia Zucchini 1 , Giulia Grisendi 1 , Leonardo Potenza 1 , Mario Luppi 1 , Jan A. Burger 3 , Silvia Deaglio 2 , Roberto Marasca 1 1 Hematology Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy 2 Department of Medical Sciences, University of Turin and Human Genetics Foundation, Turin, Italy 3 Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA * These authors have contributed equally to this work Correspondence to: Roberto Marasca, email: roberto.marasca@unimore.it Stefania Fiorcari, email: stefania.fiorcari@unimore.it Keywords: CLL, Ibrutinib, microenvironment, nurse-like cells, immune modulation Received: June 08, 2016 Accepted: August 15, 2016 Published: September 01, 2016 ABSTRACT In lymphoid organs, nurse-like cells (NLCs) show properties of tumor-associated macrophages, playing a crucial role in chronic lymphocytic leukemia (CLL) cell survival. Ibrutinib, a potent inhibitor of Bruton’s tyrosine kinase (BTK), is able to counteract pro-survival signals in CLL cells. Since the effects on CLL cells have been studied in the last years, less is known about the influence of Ibrutinib on NLCs properties. We sought to determine how Ibrutinib modifies NLCs functions focusing on the balance between immunosuppressive and inflammatory features. Our data show that Ibrutinib targets BTK expressed by NLCs modifying their phenotype and function. Treatment with Ibrutinib reduces the phagocytic ability and increases the immunosuppressive profile of NLCs exacerbating the expression of M2 markers. Accordingly, Ibrutinib hampers LPS-mediated signaling, decreasing STAT1 phosphorylation, while allows IL-4-mediated STAT6 phosphorylation. In addition, NLCs treated with Ibrutinib are able to protect CLL cells from drug-induced apoptosis partially through the secretion of IL-10. Results from patient samples obtained prior and after 1 month of treatment with Ibrutinib show an accentuation of CD206, CD11b and Tie2 in the monocytic population in the peripheral blood. Our study provides new insights into the immunomodulatory action of Ibrutinib on monocyte/macrophage population in CLL.
Steven Coutre - One of the best experts on this subject based on the ideXlab platform.
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adverse event burden in older patients with cll receiving bendamustine plus rituximab or Ibrutinib regimens alliance a041202
Leukemia, 2021Co-Authors: Steven Coutre, Jennifer R Brown, Nancy L Bartlett, Danielle M Brander, Amy S Ruppert, Allison M Booth, Wei Ding, Sreenivasa Nattam, Richard A LarsonAbstract:Ibrutinib has superior progression-free survival compared with bendamustine plus rituximab (BR) in older CLL patients, however, differences in treatment duration, six monthly BR cycles versus continuous Ibrutinib, complicate adverse event (AE) comparisons. We introduce the AE burden score (AEsc) to compare AEs, calculated for each patient by summing over products of reporting period length and grade for each all-cause grade 1-4 AE and dividing by the length of time over which AEs are assessed. A total of 176 patients received BR and 361 Ibrutinib alone or with six cycles of rituximab. At 38 months median follow-up, 64% remained on Ibrutinib. Median AEsc was higher with BR versus Ibrutinib in the first six cycles (7.2 versus 4.9, p < 0.0001). Within Ibrutinib arms, median AEsc decreased significantly to 3.7 after six cycles (p < 0.0001). 10% and 14% of BR and Ibrutinib patients discontinued treatment for AEs. In Ibrutinib arms, cumulative incidence of grade 3 or higher atrial fibrillation, hypertension, and infection (AEs of clinical interest) at 12 months was 4.5%, 17.5%, and 12.8%, respectively, and increased more slowly thereafter to 7.7%, 25.4%, and 20.5% at 36 months. Analytical tools including the AEsc and cumulative incidence of AEs can help to better characterize AE burden over time. ClinicalTrials.gov identifier: NCT01886872.
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long term efficacy and safety of first line Ibrutinib treatment for patients with cll sll 5 years of follow up from the phase 3 resonate 2 study
Leukemia, 2020Co-Authors: Jan A Burger, Steven Coutre, Alessandra Tedeschi, Paul M Barr, Tadeusz Robak, Carolyn Owen, Paolo Ghia, Osnat Bairey, Peter Hillmen, Stephen DevereuxAbstract:RESONATE-2 is a phase 3 study of first-line Ibrutinib versus chlorambucil in chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Patients aged ≥65 years (n = 269) were randomized 1:1 to once-daily Ibrutinib 420 mg continuously or chlorambucil 0.5-0.8 mg/kg for ≤12 cycles. With a median (range) follow-up of 60 months (0.1-66), progression-free survival (PFS) and overall survival (OS) benefits for Ibrutinib versus chlorambucil were sustained (PFS estimates at 5 years: 70% vs 12%; HR [95% CI]: 0.146 [0.098-0.218]; OS estimates at 5 years: 83% vs 68%; HR [95% CI]: 0.450 [0.266-0.761]). Ibrutinib benefit was also consistent in patients with high prognostic risk (TP53 mutation, 11q deletion, and/or unmutated IGHV) (PFS: HR [95% CI]: 0.083 [0.047-0.145]; OS: HR [95% CI]: 0.366 [0.181-0.736]). Investigator-assessed overall response rate was 92% with Ibrutinib (complete response, 30%; 11% at primary analysis). Common grade ≥3 adverse events (AEs) included neutropenia (13%), pneumonia (12%), hypertension (8%), anemia (7%), and hyponatremia (6%); occurrence of most events as well as discontinuations due to AEs decreased over time. Fifty-eight percent of patients continue to receive Ibrutinib. Single-agent Ibrutinib demonstrated sustained PFS and OS benefit versus chlorambucil and increased depth of response over time.
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long term follow up of the resonate phase 3 trial of Ibrutinib vs ofatumumab
Blood, 2019Co-Authors: John C Byrd, Jacqueline C Barrientos, Steven Coutre, Ulrich Jaeger, Susan Obrien, Nishitha Reddy, Stephen P. Mulligan, Constantine S Tam, Peter Hillmen, Paul M BarrAbstract:Ibrutinib, a once-daily oral inhibitor of Bruton tyrosine kinase, has greatly improved outcomes for patients with chronic lymphocytic leukemia (CLL). The phase 3 RESONATE trial, which compared single-agent Ibrutinib to ofatumumab in high-risk, relapsed patients with CLL, provided support for approval of Ibrutinib in the United States and Europe. We describe long-term follow-up of patients treated in RESONATE, where continued superiority of progression-free survival (PFS) (hazard ratio [HR], 0.133; 95% confidence interval [CI], 0.099-0.178) was observed. Overall survival benefit continues (HR, 0.591; 95% CI, 0.378-0.926), although with decreased magnitude relative to that seen before crossover to Ibrutinib was implemented for patients on ofatumumab (HR, 0.426; 95% CI, 0.220-0.823). Notably, overall response to Ibrutinib increased over time, with 91% of patients attaining a response. The PFS benefit with Ibrutinib was independent of baseline risk factors, although patients with ≥2 prior therapies had shorter PFS than those with <2 prior therapies, and the presence of TP53 or SF3B1 mutations showed a trend toward shorter PFS vs without these factors. Median duration of Ibrutinib was 41 months, with 46% remaining on treatment at a median follow-up of 44 months. Grade ≥3 adverse events generally decreased over time, causing only a small proportion of patients to cease therapy. Ibrutinib was discontinued due to progressive disease in 27% of patients. This long-term study provides support for sustained efficacy and safety of Ibrutinib in relapsed/refractory CLL and consideration of study provisions that allow crossover to investigational therapy when benefit has been clearly demonstrated. This trial was registered at www.clinicaltrials.gov as #NCT01578707.
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Extended follow-up and impact of high-risk prognostic factors from the phase 3 RESONATE study in patients with previously treated CLL/SLL
Leukemia, 2018Co-Authors: J R Brown, Steven Coutre, Cs Tam, Jc Barrientos, Nm Reddy, Sp Mulligan, P Hillmen, S O’brien, U Jaeger, Pm BarrAbstract:In the phase 3 RESONATE study, Ibrutinib demonstrated superior progression-free survival (PFS), overall survival (OS) and overall response rate (ORR) compared with ofatumumab in relapsed/refractory CLL patients with high-risk prognostic factors. We report updated results from RESONATE in these traditionally chemotherapy resistant high-risk genomic subgroups at a median follow-up of 19 months. Mutations were detected by Foundation One Heme Panel. Baseline mutations in the Ibrutinib arm included TP53 (51%), SF3B1 (31%), NOTCH1 (28%), ATM (19%) and BIRC3 (14%). Median PFS was not reached, with 74% of patients randomized to Ibrutinib alive and progression-free at 24 months. The improved efficacy of Ibrutinib vs ofatumumab continues in all prognostic subgroups including del17p and del11q. No significant difference within the Ibrutinib arm was observed for PFS across most genomic subtypes, although a subset carrying both TP53 mutation and del17p had reduced PFS compared with patients with neither abnormality. Reduced PFS or OS was not evident in patients with only del17p. PFS was significantly better for Ibrutinib-treated patients in second-line vs later lines of therapy. The robust clinical activity of Ibrutinib continues to show ongoing efficacy and acceptable safety consistent with prior reports, independent of various known high-risk mutations.
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Ibrutinib versus ofatumumab in previously treated chronic lymphocytic leukemia small lymphocytic lymphoma cll sll results from the randomized phase iii resonate pcyc 1112 trial
Clinical Lymphoma Myeloma & Leukemia, 2015Co-Authors: Jennifer R Brown, Jacqueline C Barrientos, Steven Coutre, Susan Obrien, Nishitha Reddy, Stephen P. Mulligan, John C Byrd, Neil E Kay, Constantine S Tam, Ulrich JaegerAbstract:304 Ibrutinib Versus Ofatumumab in Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): Results From the Randomized Phase III RESONATETM (PCYC-1112) Trial J Jennifer R. Brown, MD, PhD1, John C. Byrd, MD2, Susan O’Brien, MD3, Jacqueline C. Barrientos, MD4, Neil E. Kay, MD5, Nishitha M. Reddy, MBBS, MD6, Steven Coutre, MD7, Constantine S. Tam, MBBS, MD8, Stephen Mulligan, MBBS, PhD, FRACP, FRCPA9, Ulrich Jaeger, MD10, Stephen Devereux, PhD, FRCP, FRCPath11, Paul M. Barr, MD12, Richard Furman, MD13, Thomas Kipps, MD, PhD14, Florence Cymbalista, MD, PhD15, Maria Fardis, PhD, MBA16, Jesse McGreivy, MD16, Fong Clow, DSc16, Danelle F. James, MD, MAS16, Peter Hillmen, MD, PhD, FRCP, FRCPath17 1Dana-Farber Cancer Institute, Boston, MA, USA; 2The Ohio State University Medical Center, Columbus, OH, USA; 3University of Texas MD Anderson Cancer Center, Houston, TX, USA; 4North Shore Long Island Jewish Health System, Manhasset, NY, USA; 5Mayo Clinic, Rochester, MN, USA; 6Vanderbilt-Ingram Cancer Center, Nashville, TN, USA; 7Stanford University School of Medicine, Stanford, CA, USA; 8Peter MacCallum Cancer Centre and St. Vincent’s Hospital, Melbourne, Australia; 9Royal North Shore Hospital, Sydney, Australia; 10Medical University of Vienna, Vienna, Austria; 11Kings College Hospital, NHS Foundation Trust Denmark Hill, London, UK; 12University of Rochester Cancer Center, Rochester, NY, USA; 13Weill Cornell Medical College/New York Presbyterian Hospital, New York, NY, USA; 14Moores UCSD Cancer Center, San Diego, CA, USA; 15Hopital Avicenne, Paris, France; 16Pharmacyclics, Inc., Sunnyvale, CA, USA; 17The Leeds Teaching Hospitals, St. James Institute of Oncology, Leeds, UK Context: Ibrutinib, a first-in-class, once-daily oral, covalent inhibitor of Bruton’s tyrosine kinase, demonstrated single-agent activity and an acceptable safety profile in a phase II relapsed/refractory (R/R) CLL/SLL study (Byrd et al. NEJM 2013). Ibrutinib is FDA approved for CLL patients who have received ≥1 prior therapy, and for patients with del(17p) CLL. Objective: Interim safety and efficacy results from an international, multicenter, open-label, randomized phase III study of single-agent Ibrutinib vs ofatumumab in R/R CLL/SLL Patients: Patients with R/R CLL/SLL who received ≥1 previous therapy considered inappropriate for purine analogs Main Outcome Measures: Independent Review Committee-assessed PFS (primary); overall survival (OS), ORR, safety (secondary) Intervention: 420 mg oral Ibrutinib daily or IV ofatumumab 300/2000 mg (12 doses) Results: 391 patients (median age 67 years, 40% ≥70 years, 30% del17p); 195 randomized to Ibrutinib, 196 to ofatumumab. Ibrutinib patients had median 3 prior therapies vs 2 for ofatumumab. Ibrutinib significantly improved PFS (median not reached vs 8.1 months; HR 0.215, 95% CI 0.146-0.317, P<0.0001; 78.5% risk reduction), and OS (median not reached; HR 0.434, 95% CI 0.238-0.789, P=0.0049; 57% risk reduction) vs ofatumumab. Ofatumumab patients (n=57) with confirmed progressive disease crossed over to the Ibrutinib arm. ORR by IRC, including partial response with lymphocytosis: 62.6% for Ibrutinib vs 4.1% for ofatumumab. Similar effects were seen in del(17p) and purine analog-refractory subsets. Most frequent adverse events (AEs) for Ibrutinib vs ofatumumab: diarrhea (47.7% vs 17.8%), fatigue (27.7% vs 29.8%), and nausea (26.2% vs 18.3%). Any-grade atrial fibrillation was observed more frequently with Ibrutinib (5.1% vs 0.5%). Major hemorrhage rates: 1% for Ibrutinib vs 1.6% for ofatumumab. Drug discontinuation due to AEs: 4.1% for Ibrutinib vs 3.6% for ofatumumab. At median time on study of 9.6 months, 86% of Ibrutinib patients were continuing treatment. Conclusions: Single-agent Ibrutinib significantly improved PFS, OS, and ORR in patients with previously treated CLL/SLL compared with ofatumumab. The effect of Ibrutinib on PFS was observed irrespective of baseline features, including del(17p) or purine analog-refractory disease. The safety profile was comparable with that reported previously. These results support Ibrutinib as an effective therapy for patients with previously treated CLL.
Paul M Barr - One of the best experts on this subject based on the ideXlab platform.
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long term efficacy and safety of first line Ibrutinib treatment for patients with cll sll 5 years of follow up from the phase 3 resonate 2 study
Leukemia, 2020Co-Authors: Jan A Burger, Steven Coutre, Alessandra Tedeschi, Paul M Barr, Tadeusz Robak, Carolyn Owen, Paolo Ghia, Osnat Bairey, Peter Hillmen, Stephen DevereuxAbstract:RESONATE-2 is a phase 3 study of first-line Ibrutinib versus chlorambucil in chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Patients aged ≥65 years (n = 269) were randomized 1:1 to once-daily Ibrutinib 420 mg continuously or chlorambucil 0.5-0.8 mg/kg for ≤12 cycles. With a median (range) follow-up of 60 months (0.1-66), progression-free survival (PFS) and overall survival (OS) benefits for Ibrutinib versus chlorambucil were sustained (PFS estimates at 5 years: 70% vs 12%; HR [95% CI]: 0.146 [0.098-0.218]; OS estimates at 5 years: 83% vs 68%; HR [95% CI]: 0.450 [0.266-0.761]). Ibrutinib benefit was also consistent in patients with high prognostic risk (TP53 mutation, 11q deletion, and/or unmutated IGHV) (PFS: HR [95% CI]: 0.083 [0.047-0.145]; OS: HR [95% CI]: 0.366 [0.181-0.736]). Investigator-assessed overall response rate was 92% with Ibrutinib (complete response, 30%; 11% at primary analysis). Common grade ≥3 adverse events (AEs) included neutropenia (13%), pneumonia (12%), hypertension (8%), anemia (7%), and hyponatremia (6%); occurrence of most events as well as discontinuations due to AEs decreased over time. Fifty-eight percent of patients continue to receive Ibrutinib. Single-agent Ibrutinib demonstrated sustained PFS and OS benefit versus chlorambucil and increased depth of response over time.
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long term follow up of the resonate phase 3 trial of Ibrutinib vs ofatumumab
Blood, 2019Co-Authors: John C Byrd, Jacqueline C Barrientos, Steven Coutre, Ulrich Jaeger, Susan Obrien, Nishitha Reddy, Stephen P. Mulligan, Constantine S Tam, Peter Hillmen, Paul M BarrAbstract:Ibrutinib, a once-daily oral inhibitor of Bruton tyrosine kinase, has greatly improved outcomes for patients with chronic lymphocytic leukemia (CLL). The phase 3 RESONATE trial, which compared single-agent Ibrutinib to ofatumumab in high-risk, relapsed patients with CLL, provided support for approval of Ibrutinib in the United States and Europe. We describe long-term follow-up of patients treated in RESONATE, where continued superiority of progression-free survival (PFS) (hazard ratio [HR], 0.133; 95% confidence interval [CI], 0.099-0.178) was observed. Overall survival benefit continues (HR, 0.591; 95% CI, 0.378-0.926), although with decreased magnitude relative to that seen before crossover to Ibrutinib was implemented for patients on ofatumumab (HR, 0.426; 95% CI, 0.220-0.823). Notably, overall response to Ibrutinib increased over time, with 91% of patients attaining a response. The PFS benefit with Ibrutinib was independent of baseline risk factors, although patients with ≥2 prior therapies had shorter PFS than those with <2 prior therapies, and the presence of TP53 or SF3B1 mutations showed a trend toward shorter PFS vs without these factors. Median duration of Ibrutinib was 41 months, with 46% remaining on treatment at a median follow-up of 44 months. Grade ≥3 adverse events generally decreased over time, causing only a small proportion of patients to cease therapy. Ibrutinib was discontinued due to progressive disease in 27% of patients. This long-term study provides support for sustained efficacy and safety of Ibrutinib in relapsed/refractory CLL and consideration of study provisions that allow crossover to investigational therapy when benefit has been clearly demonstrated. This trial was registered at www.clinicaltrials.gov as #NCT01578707.
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single agent Ibrutinib versus chemoimmunotherapy regimens for treatment naive patients with chronic lymphocytic leukemia a cross trial comparison of phase 3 studies
American Journal of Hematology, 2018Co-Authors: Tadeusz Robak, Jan A Burger, Alessandra Tedeschi, Paul M Barr, Carolyn Owen, Osnat Bairey, Peter Hillmen, David Simpson, Sebastian Grosicki, Stephen DevereuxAbstract:Chemoimmunotherapy (CIT) and targeted therapy with single-agent Ibrutinib are both recommended first-line treatments for chronic lymphocytic leukemia (CLL), although their outcomes have not been directly compared. Using Ibrutinib data from the RESONATE-2 (PCYC-1115/1116) study conducted in patients ≥65 years without del(17p), we performed a cross-trial comparison with CIT data from published phase 3 studies in first-line treatment of CLL. Progression-free survival (PFS), overall survival (OS), and safety data for Ibrutinib (median follow-up 35.7 months) were evaluated alongside available CIT data. CIT regimens included: fludarabine + cyclophosphamide + rituximab (CLL8, CLL10), bendamustine + rituximab (CLL10), obinutuzumab + chlorambucil and rituximab + chlorambucil (CLL11), and ofatumumab + chlorambucil (COMPLEMENT-1). Median age across studies was 61-74 years, with older populations receiving Ibrutinib, obinutuzumab + chlorambucil, or rituximab + chlorambucil. Median follow-up varied across studies/regimens (range 14.5-37.4 months). Among all patients, PFS appeared longer with Ibrutinib relative to CIT and OS appeared comparable. Relative to CIT studies that similarly excluded patients with del(17p) (CLL10) or enrolled older/less-fit patients (CLL11), PFS appeared favorable for Ibrutinib in high-risk subgroups, including advanced disease, bulky lymph nodes, unmutated IGHV status, and presence of del(11q). Grade ≥ 3 infections ranged from 9% (ofatumumab + chlorambucil) to 40% (fludarabine + cyclophosphamide + rituximab), and was 25% with Ibrutinib. Grade ≥ 3 neutropenia was 12% for Ibrutinib and 26%-84% for CIT. Although definitive conclusions cannot be made due to inherent limitations of cross-trial comparisons, this report suggests that Ibrutinib has a favorable benefit/risk profile and may potentially eliminate the need for chemotherapy in some patients. Randomized, comparative studies are needed to support these findings.
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Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia
The New England Journal of Medicine, 2015Co-Authors: Jan A Burger, Alessandra Tedeschi, Paul M Barr, Tadeusz Robak, Carolyn Owen, Paolo Ghia, Osnat Bairey, Peter Hillmen, Nancy L Bartlett, David SimpsonAbstract:BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.)
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the bruton tyrosine kinase inhibitor Ibrutinib with chemoimmunotherapy in patients with chronic lymphocytic leukemia
Blood, 2015Co-Authors: Jennifer R Brown, Jacqueline C Barrientos, Jan A Burger, Paul M Barr, Ian W Flinn, Anh Tran, Fong Clow, Danelle F James, Thorsten Graef, Jonathan W FriedbergAbstract:The safety and efficacy of Ibrutinib, an oral inhibitor of Bruton tyrosine kinase, were evaluated with chemoimmunotherapy (CIT) in a multicenter phase 1b study. Patients with relapsed/refractory chronic lymphocytic leukemia received bendamustine and rituximab (BR) or fludarabine, cyclophosphamide, and rituximab (FCR) for up to 6 cycles with daily Ibrutinib (420 mg) until progressive disease or unacceptable toxicity. Enrollment to FCR-Ibrutinib closed early due to a lack of fludarabine-naive previously treated patients. No patients treated with BR-Ibrutinib (n = 30) or FCR-Ibrutinib (n = 3) experienced prolonged hematologic toxicity in cycle 1 (primary end point). Tolerability was as expected with either CIT or single-agent Ibrutinib. The overall response rate (ORR) with BR-Ibrutinib was 93.3%, including 16.7% complete responses (CRs) initially, which increased to 40% with the extension period. Including 1 patient with partial response with lymphocytosis, the best ORR was 96.7%. Sixteen of 21 patients with baseline cytopenias had sustained hematologic improvement. At 12 and 36 months, 86.3% and 70.3% remained progression-free, respectively. All 3 patients treated with Ibrutinib-FCR achieved CR. Ibrutinib may enhance CIT efficacy without additive toxicities, providing the rationale for studying this combination in an ongoing phase 3 trial. The study is registered to www.clinicaltrials.gov as #NCT01292135.
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long term efficacy and safety of first line Ibrutinib treatment for patients with cll sll 5 years of follow up from the phase 3 resonate 2 study
Leukemia, 2020Co-Authors: Jan A Burger, Steven Coutre, Alessandra Tedeschi, Paul M Barr, Tadeusz Robak, Carolyn Owen, Paolo Ghia, Osnat Bairey, Peter Hillmen, Stephen DevereuxAbstract:RESONATE-2 is a phase 3 study of first-line Ibrutinib versus chlorambucil in chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Patients aged ≥65 years (n = 269) were randomized 1:1 to once-daily Ibrutinib 420 mg continuously or chlorambucil 0.5-0.8 mg/kg for ≤12 cycles. With a median (range) follow-up of 60 months (0.1-66), progression-free survival (PFS) and overall survival (OS) benefits for Ibrutinib versus chlorambucil were sustained (PFS estimates at 5 years: 70% vs 12%; HR [95% CI]: 0.146 [0.098-0.218]; OS estimates at 5 years: 83% vs 68%; HR [95% CI]: 0.450 [0.266-0.761]). Ibrutinib benefit was also consistent in patients with high prognostic risk (TP53 mutation, 11q deletion, and/or unmutated IGHV) (PFS: HR [95% CI]: 0.083 [0.047-0.145]; OS: HR [95% CI]: 0.366 [0.181-0.736]). Investigator-assessed overall response rate was 92% with Ibrutinib (complete response, 30%; 11% at primary analysis). Common grade ≥3 adverse events (AEs) included neutropenia (13%), pneumonia (12%), hypertension (8%), anemia (7%), and hyponatremia (6%); occurrence of most events as well as discontinuations due to AEs decreased over time. Fifty-eight percent of patients continue to receive Ibrutinib. Single-agent Ibrutinib demonstrated sustained PFS and OS benefit versus chlorambucil and increased depth of response over time.
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single agent Ibrutinib versus chemoimmunotherapy regimens for treatment naive patients with chronic lymphocytic leukemia a cross trial comparison of phase 3 studies
American Journal of Hematology, 2018Co-Authors: Tadeusz Robak, Jan A Burger, Alessandra Tedeschi, Paul M Barr, Carolyn Owen, Osnat Bairey, Peter Hillmen, David Simpson, Sebastian Grosicki, Stephen DevereuxAbstract:Chemoimmunotherapy (CIT) and targeted therapy with single-agent Ibrutinib are both recommended first-line treatments for chronic lymphocytic leukemia (CLL), although their outcomes have not been directly compared. Using Ibrutinib data from the RESONATE-2 (PCYC-1115/1116) study conducted in patients ≥65 years without del(17p), we performed a cross-trial comparison with CIT data from published phase 3 studies in first-line treatment of CLL. Progression-free survival (PFS), overall survival (OS), and safety data for Ibrutinib (median follow-up 35.7 months) were evaluated alongside available CIT data. CIT regimens included: fludarabine + cyclophosphamide + rituximab (CLL8, CLL10), bendamustine + rituximab (CLL10), obinutuzumab + chlorambucil and rituximab + chlorambucil (CLL11), and ofatumumab + chlorambucil (COMPLEMENT-1). Median age across studies was 61-74 years, with older populations receiving Ibrutinib, obinutuzumab + chlorambucil, or rituximab + chlorambucil. Median follow-up varied across studies/regimens (range 14.5-37.4 months). Among all patients, PFS appeared longer with Ibrutinib relative to CIT and OS appeared comparable. Relative to CIT studies that similarly excluded patients with del(17p) (CLL10) or enrolled older/less-fit patients (CLL11), PFS appeared favorable for Ibrutinib in high-risk subgroups, including advanced disease, bulky lymph nodes, unmutated IGHV status, and presence of del(11q). Grade ≥ 3 infections ranged from 9% (ofatumumab + chlorambucil) to 40% (fludarabine + cyclophosphamide + rituximab), and was 25% with Ibrutinib. Grade ≥ 3 neutropenia was 12% for Ibrutinib and 26%-84% for CIT. Although definitive conclusions cannot be made due to inherent limitations of cross-trial comparisons, this report suggests that Ibrutinib has a favorable benefit/risk profile and may potentially eliminate the need for chemotherapy in some patients. Randomized, comparative studies are needed to support these findings.
