Showing papers by "Jan A. Burger published in 2023"
TL;DR: In the phase 3 RESONATE-2 study as mentioned in this paper , the authors described characteristics and outcomes of patients who received long-term treatment with ibrutinib for ≥5 years.
Abstract: Simple Summary Ibrutinib is an established standard of care in the first-line treatment of chronic lymphocytic leukemia. Since ibrutinib is given continuously, data on long-term treatment, outcomes, and safety are essential to inform clinical decision making. Here, we describe characteristics and outcomes of patients who received long-term treatment with ibrutinib for ≥5 years in the phase 3 RESONATE-2 study. More than half (58%) of the patients randomly assigned to receive ibrutinib in the RESONATE-2 study continued to benefit from ibrutinib treatment for ≥5 years, regardless of baseline characteristics. Among patients who were on ibrutinib treatment for ≥5 years, complete response rates improved over time through the 5 years. The safety profile of ibrutinib treatment for ≥5 years was consistent with previous reports and no new safety signals were identified. For patients who experienced adverse events, dose modification was effective in resolving adverse events, thereby facilitating continued treatment. Abstract Primary results from the phase 3 RESONATE-2 study demonstrated superior efficacy and tolerability with ibrutinib versus chlorambucil in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Here, we describe characteristics and outcomes of patients who received ibrutinib treatment for ≥5 years in RESONATE-2. Patients aged ≥65 years with previously untreated CLL/SLL, without del(17p), were randomly assigned 1:1 to once-daily ibrutinib 420 mg until disease progression/unacceptable toxicity (n = 136) or chlorambucil 0.5–0.8 mg/kg for ≤12 cycles (n = 133). Baseline characteristics in ibrutinib-randomized patients (n = 136) were generally similar between patients on ibrutinib treatment for ≥5 years (n = 79) versus those on treatment for <5 years (n = 57). In patients on ibrutinib treatment for ≥5 years, complete response rates improved over time, reaching 42% by 5 years. Estimated 7-year progression-free survival and overall survival rates were 82% and 94%, respectively. Adverse events (AEs) led to dose reductions in 16/79 patients (20%); these AEs were resolved for 13/16 patients (81%). AEs led to dose holds (≥7 days) in 45/79 patients (57%); these AEs were resolved for 43/45 patients (96%). More than half (58%) of ibrutinib-randomized patients benefitted from ibrutinib treatment for ≥5 years regardless of baseline characteristics. Dose modification resolved AEs for most patients, thereby facilitating continued treatment.
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TL;DR: In this article , the authors analyzed the incidence of major bleeding in 64 patient exposures that received ibrutinib with concomitant therapeutic anticoagulation, and the highest incidence was observed with rivaroxaban (3/17, 18%), followed by apixaban (2/35, 6%).
Abstract: Increased rates of clinically significant bleeding have been reported with ibrutinib, however, limited data is available on the risk when given with concomitant therapeutic anticoagulation. We analyzed the incidence of major bleeding in 64 patient exposures that received ibrutinib with concomitant therapeutic anticoagulation. Major bleeding was observed in 5/64 (8%) patient exposures. The highest incidence was observed with rivaroxaban (3/17, 18%), followed by apixaban (2/35, 6%). No major bleeding events were seen with enoxaparin (n = 10). A total of 38% of patient exposures received a concomitant antiplatelet agent along with therapeutic anticoagulation. Among these patients, one (4%) experienced a fatal hemorrhage while taking ibrutinib, apixaban, and clopidogrel concomitantly. Our retrospective study observed a higher rate of major hemorrhage with combined DOAC with ibrutinib than historically reported with ibrutinib alone. This combination may be associated with increased risk of major bleeding and further prospective studies evaluating this risk are necessary.
TL;DR: In this article , the authors measured protein expression levels of 16 DNADR and DDR proteins using the Reverse Phase Protein Array methodology in acute myeloid (AML) (n = 1310), T-cell acute lymphoblastic leukemia (T-ALL) (N = 361) and chronic lymphocytic leukemia (CLL)(n = 795) cases.
Abstract: DNA damage response (DNADR) recognition and repair (DDR) pathways affect carcinogenesis and therapy responsiveness in cancers, including leukemia. We measured protein expression levels of 16 DNADR and DDR proteins using the Reverse Phase Protein Array methodology in acute myeloid (AML) (n = 1310), T-cell acute lymphoblastic leukemia (T-ALL) (n = 361) and chronic lymphocytic leukemia (CLL) (n = 795) cases. Clustering analysis identified five protein expression clusters; three were unique compared to normal CD34+ cells. Individual protein expression differed by disease for 14/16 proteins, with five highest in CLL and nine in T-ALL, and by age in T-ALL and AML (six and eleven proteins, respectively), but not CLL (n = 0). Most (96%) of the CLL cases clustered in one cluster; the other 4% were characterized by higher frequencies of deletion 13q and 17p, and fared poorly (p < 0.001). T-ALL predominated in C1 and AML in C5, but both occurred in all four acute-dominated clusters. Protein clusters showed similar implications for survival and remission duration in pediatric and adult T-ALL and AML populations, with C5 doing best in all. In summary, DNADR and DDR protein expression was abnormal in leukemia and formed recurrent clusters that were shared across the leukemias with shared prognostic implications across diseases, and individual proteins showed age- and disease-related differences.
TL;DR: In this article , the authors reported the first case of Membranous Nephropathy (MN) in a patient with CLL treated with ibrutinib with complete renal response.
Abstract: Membranous nephropathy (MN) is an uncommon renal presentation in patients with chronic lymphocytic leukemia (CLL), and as such, there is no standard therapy for these patients. A few cases of MN in CLL have been described with varying success in MN treatment involving alkylating agents and fludarabine. Here we report the first case of MN in a patient with CLL treated with ibrutinib with complete renal response. This presentation underlines the importance of recognizing rare glomerular diseases that may occur with CLL and offers a new therapeutic avenue to the treatment of CLL-associated MN.
TL;DR: The RESONATE-2 study as mentioned in this paper showed that more participants who took ibrutinib (59%) were alive without worsening of their disease at 7-years after starting treatment than those who took chlorambucil (9%).
Abstract: WHAT IS THIS SUMMARY ABOUT?
This is a plain language summary of a publication describing long-term results from the RESONATE-2 study with up to 8 years of follow-up. The original paper was published in Blood Advances in June 2022.
WHAT WERE THE RESULTS?
Researchers looked at 269 adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who had not received any treatment for their CLL/SLL. Study participants were randomly divided into two groups: 136 participants received treatment with a drug called ibrutinib, and 133 participants received treatment with a drug called chlorambucil. Participants in the study were treated and followed for up to 8 years, with results showing that more participants who took ibrutinib (59%) were alive without worsening of their disease at 7 years after starting treatment than participants who took chlorambucil (9%). Almost half of the participants (42%) were able to stay on ibrutinib treatment for up to 8 years.
WHAT DO THE RESULTS OF THE STUDY MEAN?
In people with CLL or SLL, more participants who were taking ibrutinib were alive without worsening of their disease after 7 years compared with participants who took chlorambucil. Clinical Trial Registration: NCT01722487 (ClinicalTrials.gov) Clinical Trial Registration: NCT01724346 (ClinicalTrials.gov).
TL;DR: In this article , the authors evaluated outcomes with dose reductions in Ibr-treated patients with cardiac AEs, and found that cardiac AE recurrence was not negatively impacted by dose reduction, both overall (n=22, median PFS not reached [NR], 24-mo PFS: 91%, and in those who started with the 420 mg Ibr dose.
Abstract: 7538 Background: Continuous therapy with once-daily ibrutinib (Ibr) is associated with long-term PFS in pts with B-cell malignancies. Dose reduction is a potential AE management approach that may optimize treatment outcomes. We evaluated outcomes with dose reductions in Ibr-treated pts with cardiac AEs. Methods: Data were pooled for Ibr-treated pts from 10 studies of CLL (n=781), mantle cell lymphoma (MCL; n=250), marginal zone lymphoma (MZL; n=63) or Waldenström macroglobulinemia (WM; n=169). Cardiac AEs, initial and recurrent, were identified by preferred terms within the cardiac disorders system organ class. Recurrence was defined as an AE of same or worse grade, and was measured up to 30 days after last dose of ibrutinib or start of next-line therapy, whichever occurred earlier. Results: Overall, 234/1263 pts (19%) had cardiac AEs of any grade. Twelve pts were excluded from the analysis: 9 who had a dose reduction prior to a cardiac AE (0.7%) and 3 who had a fatal cardiac AE with no prior cardiac AE (0.2%). Of the remaining 222 pts with grade 1-4 cardiac AEs, 22 (10%) had Ibr dose reduction to 420 mg (n=3), 280 mg (n=10), or 140 mg (n=9) after a cardiac AE. These pts (n=22) tended to be older (≥75 y: 45% vs 29%), less heavily pretreated (≥1 prior therapy: 45% vs 73%), and with a lower Ibr discontinuation rate (23% vs 48%) than those without dose reduction (n=200). Recurrence of the same cardiac AEs at the same or worse severity was less frequent in pts with dose reductions, both overall (14% vs 18%) and as serious AEs (5% vs 10%). No pt died due to cardiac AE recurrence. Among pts with cardiac AEs who started with the 420 mg Ibr dose (177/222; excludes 45 patients with MCL or MZL who per label start with 560 mg dose), no cardiac AE recurred at same or worse severity in the subset with dose reductions (Table). PFS was not negatively impacted by dose reduction, both overall (n=22; median PFS not reached [NR], 24-mo PFS: 91%), and in those who started with the 420 mg dose (n=18; median PFS NR; 24-mo PFS, 94%). Conclusions: Dose reduction for cardiac AEs may enable pts to continue to benefit from long-term Ibr and mitigate the risk of cardiac AE recurrence or worsening. Clinical trial information: NCT01105247 , NCT01236391 , NCT01578707 , NCT01722487 , NCT01611090 . [Table: see text]
TL;DR: Proteomic DNA Damage Repair (DDR) expression patterns in chronic Lymphocytic Leukemia were characterized by quantifying and clustering 24 total and phosphorylated DDR proteins as mentioned in this paper .
Abstract: Proteomic DNA Damage Repair (DDR) expression patterns in Chronic Lymphocytic Leukemia were characterized by quantifying and clustering 24 total and phosphorylated DDR proteins. Overall, three protein expression patterns (C1-C3) were identified and were associated as an independent predictor of distinct patient overall survival outcomes. Patients within clusters C1 and C2 had poorer survival outcomes and responses to fludarabine, cyclophosphamide, and rituxan chemotherapy compared to patients within cluster C3. However, DDR protein expression patterns were not prognostic in more modern therapies with BCL2 inhibitors or a BTK/PI3K inhibitor. Individually, nine of the DDR proteins were prognostic for predicting overall survival and/or time to first treatment. When looking for other proteins that may be associated with or influenced by DDR expression patterns, our differential expression analysis found that cell cycle and adhesion proteins were lower in clusters compared to normal CD19 controls. In addition, cluster C3 had a lower expression of MAPK proteins compared to the poor prognostic patient clusters thus implying a potential regulatory connection between adhesion, cell cycle, MAPK, and DDR signaling in CLL. Thus, assessing the proteomic expression of DNA damage proteins in CLL provided novel insights for deciphering influences on patient outcomes and expanded our understanding of the potential complexities and effects of DDR cell signaling.
TL;DR: In this paper , the authors evaluated outcomes of Bruton's tyrosine kinase inhibitor (BTKi) treatment in pts with R/R CLL by comparing the efficacy of Ibr in RESONATE to ALPINE and ELEVATE-RR using a matching-adjusted indirect comparison analysis.
Abstract: Introduction: Ibr is a standard therapy for CLL with demonstrated efficacy in first-line and R/R settings. Within R/R CLL, single-agent Ibr was evaluated in 3 randomized phase 3 trials: RESONATE (vs. ofatumumab), ALPINE (vs. zanubrutinib), and ELEVATE-RR (vs acalabrutinib in pts with del(11q) or del(17p)). This analysis evaluated outcomes of Bruton’s tyrosine kinase inhibitor (BTKi) treatment in pts with R/R CLL by comparing the efficacy of Ibr in RESONATE to ALPINE and ELEVATE-RR using a matching-adjusted indirect comparison analysis. Methods: Individual patient data (IPD) of Ibr-treated pts from RESONATE (NCT01578707) were separately match-adjusted to Ibr-treated arms of 1) ALPINE (NCT03734016) and 2) ELEVATE-RR (NCT02477696) for key baseline characteristics: age ≥75 y, bulky disease, ≥3 or ≥4 prior treatments, b2 microglobulin >3.5 mg/L, and del(11q) or del(17p). For comparison with ELEVATE-RR, only pts with del(17p) or del(11q) from RESONATE were included. After matching, adjusted ORR (CR + CRi + nPR + PR) and PFS from RESONATE were compared with published outcomes from ALPINE and ELEVATE-RR; for PFS, IPD for ALPINE and ELEVATE-RR were extracted from published Kaplan-Meier curves. Hazard ratios (HRs) were calculated using a weighted Cox model. Results: The analysis comprised 785 Ibr-treated pts across RESONATE (n = 195), ALPINE (n = 325), and ELEVATE-RR (n = 265). After omission of pts with missing values and the adjustment procedure, the effective RESONATE sample size was 95 pts (vs ALPINE) and 69 pts (vs ELEVATE-RR). Median follow-up was 36.0 versus 29.6 mo (RESONATE adjusted vs. ALPINE published) and 36.1 versus 40.9 mo (RESONATE adjusted vs. ELEVATE-RR published). 2-y PFS (95% CI) for Ibr-treated pts in RESONATE adjusted sample and ALPINE was 81% (74–90) and 66% (60–71), respectively; median PFS was 40.7 and 34.2 mo, with an HR (95% CI) of 0.57 (0.39–0.84) favoring RESONATE, P = 0.0048 (Figure). ORR (95% CI) was 90% (86–94) and 74% (69–79), respectively (P < 0.0001). Compared with the ELEVATE-RR Ibr arm, which included more pts with high-risk genetic features than ALPINE, the RESONATE adjusted sample had greater 2-y PFS (79% [69–89] vs. 69% [64–75], not statistically significant). Median PFS was 41.2 vs. 44.1 mo (HR [95% CI] 0.85 [0.55–1.31], P = 0.46), respectively; ORR was 89% (83–95) and 80% (75–85) (P = 0.0381). Encore Abstract - previously submitted to EHA 2023 The research was funded by: The research was funded by Pharmacyclics LLC, an AbbVie Company. Keywords: Chronic Lymphocytic Leukemia (CLL), Molecular Targeted Therapies Conflicts of interests pertinent to the abstract. P. Ghia Consultant or advisory role: AbbVie, AstraZeneca, BeiGene, Merck Sharp & Dohme, Bristol Myers Squibb, Janssen, Eli Lilly/Loxo Oncology, and Roche Honoraria: AbbVie, AstraZeneca, BeiGene, Merck Sharp & Dohme, Bristol Myers Squibb, Janssen, Eli Lilly/Loxo Oncology, and Roche Research funding: AbbVie, AstraZeneca, and Janssen T. Munir Consultant or advisory role: Morphosys and Sunesis Honoraria: AbbVie, AstraZeneca, Gilead, Janssen, and Novartis Other remuneration: travel/accommodation expenses from AbbVie, Gilead, or Janssen J. Burger Consultant or advisory role: BeiGene, Gilead, Janssen, Pharmacyclics, LLC, an AbbVie company, and TG Therapeutics Honoraria: Gilead, Janssen, Novartis, Pharmacyclics, LLC, an AbbVie company, and TG Therapeutics Other remuneration: travel/accommodation expenses from Gilead, Janssen, Pharmacyclics, LLC, an AbbVie company, and TG Therapeutics J. F. Seymour Research funding: AbbVie, Celgene, Janssen, and F. Hoffmann-La Roche Ltd. Other remuneration: speakers’ bureau with AbbVie, Celgene, and F. Hoffmann-La Roche Ltd.; patents, royalties, or other intellectual property with AbbVie; and expert testimony for F. Hoffmann-La Roche Ltd. K. Rogers Consultant or advisory role: Acerta Pharma, AstraZeneca, Beigene, Genentech, Innate Pharma, and Pharmacyclics, LLC, an AbbVie company Research funding: AbbVie, Genentech, Janssen, and Novartis Other remuneration: travel/accommodation expenses from AstraZeneca H. Huang Employment or leadership position: Everest Clinical Research and AbbVie Consultant or advisory role: Everest Clinical Research and AbbVie Research funding: Everest Clinical Research and AbbVie C. Moreno Consultant or advisory role: AbbVie, Ascentage, AstraZeneca, and Janssen Research funding: AbbVie and Janssen Other remuneration: speakers’ bureau for Janssen L. Neumayr Employment or leadership position: AbbVie Consultant or advisory role: ApoPharma Stock ownership: AbbVie Honoraria: Novartis Research funding: Pfizer and Sancilio Other remuneration: travel accommodations from Forma Therapeutics C. Abbazio Employment or leadership position: AbbVie Stock ownership: AbbVie and Bristol Myers Squibb J. Sharman Consultant or advisory role: AbbVie, AstraZeneca, and BeiGene Honoraria: AbbVie, ADC Therapeutics, AstraZeneca, BeiGene, Genentech, Lilly, Pharmacyclics, LLC, an AbbVie company, and TG Therapeutics