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Ahmed Salem - One of the best experts on this subject based on the ideXlab platform.
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Semimechanistic Modeling to Guide Venetoclax Coadministration with Ritonavir and Digoxin
Clinical and translational science, 2020Co-Authors: Ali A. Alhadab, Ahmed Salem, Kevin J. FreiseAbstract:Venetoclax is a cytochrome P450, family 3, subfamily A (CYP3A) substrate and was shown to inhibit P-gp efflux transporters in vitro. To quantify the impact of CYP3A inhibition by ritonavir on Venetoclax disposition and P-gp inhibition by Venetoclax on digoxin pharmacokinetics, two semimechanistic drug-drug interaction (DDI) models of Venetoclax were developed using clinical data from healthy volunteers who received subtherapeutic doses of Venetoclax with ritonavir 50-100 mg or digoxin 0.5 mg. These models were then used to assess the magnitude of interaction at therapeutic Venetoclax doses and to explore various clinical dosing strategies that maintain Venetoclax and digoxin concentrations within their respective therapeutic windows. Simulations demonstrated that Venetoclax dose reductions of at least 75% are needed when Venetoclax is coadministered with ritonavir and administering digoxin at least 2 hours before Venetoclax would minimize DDI. Semimechanistic modeling leveraging clinical data is a plausible approach to predict DDI and propose dose adjustments, and administration time of interacting drugs.
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Model-Informed Dosing of Venetoclax in Healthy Subjects: An Exposure-Response Analysis.
Clinical and translational science, 2019Co-Authors: Nimita Dave, Sathej Gopalakrishnan, Sven Mensing, Ahmed SalemAbstract:Venetoclax is an approved drug for the treatment of some hematological malignancies. Venetoclax can cause reduction in B-lymphocyte counts as an on-target effect. The purpose of this analysis is to quantify the relationship between Venetoclax exposure and B-lymphocyte levels to inform dosing of Venetoclax in healthy subjects. Data were pooled from 10 studies in healthy subjects with Venetoclax doses ranging from 10 mg to 400 mg and food ranging from fasting to high-fat meals. Venetoclax pharmacokinetics (PK) was characterized in 203 subjects using a population approach, as implemented in NONMEM version 7.3 (Icon Development Solutions, Ellicott City, MD, USA). A semimechanistic pharmacodynamic (PD) model with a linear drug effect was fit to the B-lymphocyte data to determine the exposure-response relationship. The population PK and PD model described the observed data adequately. The 200 and 400 mg doses were shown to reduce the B-lymphocyte levels by 24% (15-35%) and 38% (25-54%), respectively. B-lymphocytes recovered to normal levels within an average of 48 (21-64) days and 59 (30-66) days, respectively, with 200 and 400 mg doses. Venetoclax can be safely administered in healthy subjects. The PK-PD model characterized the relationship between Venetoclax exposure and reduction in B-lymphocytes and will help design future Venetoclax studies in healthy subjects.
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Pharmacokinetics of the BCL-2 Inhibitor Venetoclax in Subjects with Hepatic Impairment.
Clinical Pharmacokinetics, 2019Co-Authors: Ahmed Salem, Thomas Marbury, Nimita Dave, Dale Miles, Suresh Agarwal, Orlando F. Bueno, Rajeev M MenonAbstract:INTRODUCTION Venetoclax is a selective B cell lymphoma-2 inhibitor. It is approved for treatment of chronic lymphocytic leukemia and is being investigated for other hematological malignancies. Venetoclax is predominantly eliminated by the liver; therefore, there is a need to investigate the effect of hepatic insufficiency on Venetoclax pharmacokinetics. METHODS A phase I study was carried out in 24 women with normal hepatic function or mild, moderate, or severe hepatic impairment (based on Child-Pugh scores), who received a single 50 mg dose of Venetoclax with a low-fat meal. Blood samples were collected up to 120 h after Venetoclax administration. Pharmacokinetic parameters were estimated using non-compartmental methods. RESULTS Venetoclax maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) in subjects with mild or moderate hepatic impairment were similar to subjects with normal hepatic function. Mean Venetoclax AUC in subjects with severe hepatic impairment was 2.3- to 2.7-fold higher than in subjects with normal hepatic function. The half-life of Venetoclax in subjects with severe hepatic impairment was approximately two-fold longer than in subjects with normal hepatic function and subjects with mild or moderate hepatic impairment. Unbound fractions of Venetoclax in subjects with mild, moderate, and severe hepatic impairment were similar to the subjects with normal hepatic function. No significant adverse safety events were reported. CONCLUSIONS No Venetoclax dosage adjustment is required in subjects with mild or moderate hepatic impairment. In subjects with severe hepatic impairment, a 50% dose reduction of Venetoclax is recommended to account for higher exposures and the longer half-life.
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Effect of Azithromycin on Venetoclax Pharmacokinetics in Healthy Volunteers: Implications for Dosing Venetoclax with P-gp Inhibitors.
Advances in therapy, 2018Co-Authors: Suresh Agarwal, Rajeev M Menon, Orlando F. Bueno, Bo Tong, Ahmed SalemAbstract:Venetoclax, a substrate of cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp), is approved for the treatment of patients with chronic lymphocytic leukemia who have received at least one prior therapy. This study evaluated the effect of azithromycin, a commonly used antibiotic in cancer patients and a P-gp inhibitor, on the pharmacokinetics of Venetoclax. In this single-center, open-label, nonfasting, two-period study, 12 healthy female subjects received a single 100 mg dose of Venetoclax on day 1 of period 1 and day 3 of period 2. Subjects received azithromycin 500 mg on day 1 and 250 mg once daily on days 2 through 5. Serial blood samples for the determination of Venetoclax concentrations were collected after dosing in both periods. Safety was evaluated throughout the study. Following coadministration of Venetoclax with multiple doses of azithromycin, Venetoclax maximum concentration and area under the curve to infinite time were 25% and 35% lower, respectively, compared to Venetoclax administered alone. Venetoclax half-life and time to maximum concentration remained relatively unchanged when administered with azithromycin. Venetoclax was well tolerated with no serious adverse events reported. The modest changes in Venetoclax exposures when given with azithromycin indicate that no dose adjustment would be needed when Venetoclax is coadministered with azithromycin or other drugs with P-gp inhibitory potential. Azithromycin represents an alternative to other antimicrobial agents with higher potential to alter Venetoclax pharmacokinetics such as clarithromycin, erythromycin, and ciprofloxacin. AbbVie in collaboration with Genentech/Roche.
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Pharmacokinetics of the BCL-2 Inhibitor Venetoclax in Healthy Chinese Subjects.
Clinical pharmacology in drug development, 2017Co-Authors: Tommy Tsang Cheung, Rajeev M Menon, Ahmed Salem, Orlando F. Bueno, Wijith Munasinghe, Suresh AgarwalAbstract:Venetoclax has been approved in the United States, Europe, Canada, and Australia for appropriate patients with difficult-to-treat chronic lymphocytic leukemia (CLL). The objective of this phase 1 study was to evaluate the pharmacokinetics of Venetoclax in Chinese subjects to inform the dose selection of Venetoclax in a phase 2 study of patients with relapsed/refractory (R/R) CLL in China. Twelve healthy first-generation Han Chinese subjects received a single 100-mg dose of Venetoclax following a low-fat breakfast. Pharmacokinetic parameters were estimated using noncompartmental methods. After a single dose of Venetoclax in healthy Chinese subjects, the median time to peak concentration was 6 hours (range, 4 to 6 hours), and the mean ± SD Cmax , AUCinf , and terminal half-life were 1.0 ± 0.32 μg/mL, 12.6 ± 5.4 μg·h/mL, and 18.4 ± 2.97 hours, respectively. On average, Venetoclax Cmax and AUCinf values were 94% and 66% higher, respectively, in Chinese subjects compared with those observed historically for non-Asian subjects receiving the same dose. Based on these pharmacokinetic results and the established exposure-response relationship of Venetoclax in non-Asian CLL subjects, a 400-mg once-daily dosage regimen was selected for evaluating the Venetoclax pharmacokinetics, efficacy, and safety in the Venetoclax phase 2 open-label study in Chinese subjects with R/R CLL.
Suresh Agarwal - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetics of the BCL-2 Inhibitor Venetoclax in Subjects with Hepatic Impairment.
Clinical Pharmacokinetics, 2019Co-Authors: Ahmed Salem, Thomas Marbury, Nimita Dave, Dale Miles, Suresh Agarwal, Orlando F. Bueno, Rajeev M MenonAbstract:INTRODUCTION Venetoclax is a selective B cell lymphoma-2 inhibitor. It is approved for treatment of chronic lymphocytic leukemia and is being investigated for other hematological malignancies. Venetoclax is predominantly eliminated by the liver; therefore, there is a need to investigate the effect of hepatic insufficiency on Venetoclax pharmacokinetics. METHODS A phase I study was carried out in 24 women with normal hepatic function or mild, moderate, or severe hepatic impairment (based on Child-Pugh scores), who received a single 50 mg dose of Venetoclax with a low-fat meal. Blood samples were collected up to 120 h after Venetoclax administration. Pharmacokinetic parameters were estimated using non-compartmental methods. RESULTS Venetoclax maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) in subjects with mild or moderate hepatic impairment were similar to subjects with normal hepatic function. Mean Venetoclax AUC in subjects with severe hepatic impairment was 2.3- to 2.7-fold higher than in subjects with normal hepatic function. The half-life of Venetoclax in subjects with severe hepatic impairment was approximately two-fold longer than in subjects with normal hepatic function and subjects with mild or moderate hepatic impairment. Unbound fractions of Venetoclax in subjects with mild, moderate, and severe hepatic impairment were similar to the subjects with normal hepatic function. No significant adverse safety events were reported. CONCLUSIONS No Venetoclax dosage adjustment is required in subjects with mild or moderate hepatic impairment. In subjects with severe hepatic impairment, a 50% dose reduction of Venetoclax is recommended to account for higher exposures and the longer half-life.
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Effect of Azithromycin on Venetoclax Pharmacokinetics in Healthy Volunteers: Implications for Dosing Venetoclax with P-gp Inhibitors.
Advances in therapy, 2018Co-Authors: Suresh Agarwal, Rajeev M Menon, Orlando F. Bueno, Bo Tong, Ahmed SalemAbstract:Venetoclax, a substrate of cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp), is approved for the treatment of patients with chronic lymphocytic leukemia who have received at least one prior therapy. This study evaluated the effect of azithromycin, a commonly used antibiotic in cancer patients and a P-gp inhibitor, on the pharmacokinetics of Venetoclax. In this single-center, open-label, nonfasting, two-period study, 12 healthy female subjects received a single 100 mg dose of Venetoclax on day 1 of period 1 and day 3 of period 2. Subjects received azithromycin 500 mg on day 1 and 250 mg once daily on days 2 through 5. Serial blood samples for the determination of Venetoclax concentrations were collected after dosing in both periods. Safety was evaluated throughout the study. Following coadministration of Venetoclax with multiple doses of azithromycin, Venetoclax maximum concentration and area under the curve to infinite time were 25% and 35% lower, respectively, compared to Venetoclax administered alone. Venetoclax half-life and time to maximum concentration remained relatively unchanged when administered with azithromycin. Venetoclax was well tolerated with no serious adverse events reported. The modest changes in Venetoclax exposures when given with azithromycin indicate that no dose adjustment would be needed when Venetoclax is coadministered with azithromycin or other drugs with P-gp inhibitory potential. Azithromycin represents an alternative to other antimicrobial agents with higher potential to alter Venetoclax pharmacokinetics such as clarithromycin, erythromycin, and ciprofloxacin. AbbVie in collaboration with Genentech/Roche.
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Pharmacokinetics of the BCL-2 Inhibitor Venetoclax in Healthy Chinese Subjects.
Clinical pharmacology in drug development, 2017Co-Authors: Tommy Tsang Cheung, Rajeev M Menon, Ahmed Salem, Orlando F. Bueno, Wijith Munasinghe, Suresh AgarwalAbstract:Venetoclax has been approved in the United States, Europe, Canada, and Australia for appropriate patients with difficult-to-treat chronic lymphocytic leukemia (CLL). The objective of this phase 1 study was to evaluate the pharmacokinetics of Venetoclax in Chinese subjects to inform the dose selection of Venetoclax in a phase 2 study of patients with relapsed/refractory (R/R) CLL in China. Twelve healthy first-generation Han Chinese subjects received a single 100-mg dose of Venetoclax following a low-fat breakfast. Pharmacokinetic parameters were estimated using noncompartmental methods. After a single dose of Venetoclax in healthy Chinese subjects, the median time to peak concentration was 6 hours (range, 4 to 6 hours), and the mean ± SD Cmax , AUCinf , and terminal half-life were 1.0 ± 0.32 μg/mL, 12.6 ± 5.4 μg·h/mL, and 18.4 ± 2.97 hours, respectively. On average, Venetoclax Cmax and AUCinf values were 94% and 66% higher, respectively, in Chinese subjects compared with those observed historically for non-Asian subjects receiving the same dose. Based on these pharmacokinetic results and the established exposure-response relationship of Venetoclax in non-Asian CLL subjects, a 400-mg once-daily dosage regimen was selected for evaluating the Venetoclax pharmacokinetics, efficacy, and safety in the Venetoclax phase 2 open-label study in Chinese subjects with R/R CLL.
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pharmacokinetics of Venetoclax a novel bcl 2 inhibitor in patients with relapsed or refractory chronic lymphocytic leukemia or non hodgkin lymphoma
The Journal of Clinical Pharmacology, 2017Co-Authors: Ahmed Salem, Suresh Agarwal, Martin Dunbar, Rod A. Humerickhouse, Sari H. Enschede, Shekman WongAbstract:Venetoclax is a selective BCL-2 inhibitor that is approved in the United States for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion who have received at least 1 prior therapy. The aim of this analysis was to characterize Venetoclax pharmacokinetics in the plasma and urine of patients with hematological malignancies and evaluate the effect of dose proportionality, accumulation, weak and moderate CYP3A inhibitors, as well as low- and high-fat meals on Venetoclax pharmacokinetics. Patients received a once-daily Venetoclax dose of 20 to 1200 mg. Pharmacokinetic parameters were estimated using noncompartmental methods. Venetoclax peak exposures were achieved at 5 to 8 hours under low-fat conditions, and the mean terminal-phase elimination half-life ranged between 14.1 and 18.2 hours at different doses. Venetoclax steady-state exposures showed minimal accumulation and increased proportionally over the dose range of 300 to 900 mg. Low-fat and high-fat meals increased Venetoclax exposures by approximately 4-fold relative to the fasting state. Moderate CYP3A inhibitors increased Venetoclax exposures by 40% to 60%, whereas weak CYP3A inhibitors had no effect. A negligible amount of Venetoclax was excreted in the urine. In summary, Venetoclax exhibits a pharmacokinetic profile that is compatible with once-daily dosing with food regardless of fat content. Concomitant use of Venetoclax with moderate CYP3A inhibitors should be avoided or Venetoclax dose should be reduced during the Venetoclax initiation and ramp-up phase in CLL patients. Renal excretion plays a minimal role in the elimination of Venetoclax.
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Management of Venetoclax-Posaconazole Interaction in Acute Myeloid Leukemia Patients: Evaluation of Dose Adjustments
Clinical therapeutics, 2017Co-Authors: Suresh Agarwal, Rajeev M Menon, Courtney D. Dinardo, Jalaja Potluri, Martin Dunbar, Hagop M. Kantarjian, Rod A. Humerickhouse, Shekman Wong, Marina Konopleva, Ahmed SalemAbstract:Abstract Purpose The effect of posaconazole, a strong cytochrome P450 3A (CYP3A) inhibitor and commonly used antifungal agent, on the pharmacokinetic properties of Venetoclax, a CYP3A substrate, was evaluated in patients with acute myeloid leukemia to determine the dose adjustments needed to manage this potential interaction. Methods Twelve patients received 20- to 200-mg ramp-up treatment with oral Venetoclax and 20 mg/m 2 of intravenous decitabine on days 1 through 5, followed by 400 mg of Venetoclax alone on days 6 through 20. On days 21 through 28, patients received 300 mg of posaconazole plus reduced doses of Venetoclax (50 or 100 mg) to account for expected increases in Venetoclax plasma concentrations. Blood samples were collected before dosing and up to 24 hours after the Venetoclax dose on days 20 and 28. Findings Compared with a Venetoclax dose of 400 mg when administered alone (day 20), coadministration of Venetoclax at a 50-mg dose with multiple doses of posaconazole increased mean Venetoclax C max and AUC 0–24 by 53% and 76%, respectively, whereas coadministration of Venetoclax at a 100-mg dose with posaconazole increased mean Venetoclax C max and AUC 0–24 by 93% and 155%, respectively. When adjusted for different doses and nonlinearity, posaconazole was estimated to increase Venetoclax C max and AUC 0–24 by 7.1- and 8.8-fold, respectively. Both the 50- and 100-mg Venetoclax doses administered with posaconazole were well tolerated. Implications The results are consistent with inhibition of CYP3A-mediated metabolism of Venetoclax. Posaconazole can be used for antifungal prophylaxis in patients with acute myeloid leukemia receiving Venetoclax after reducing the Venetoclax dose by at least 75%. ClinicalTrials.gov identifier: NCT02203773.
John F. Seymour - One of the best experts on this subject based on the ideXlab platform.
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BTK inhibitor therapy is effective in patients with CLL resistant to Venetoclax.
Blood, 2020Co-Authors: Victor S Lin, Piers Blombery, Tamia Nguyen, Thomas E. Lew, Sasanka M. Handunnetti, David A. Westerman, Bryone J. Kuss, Constantine S. Tam, Andrew W. Roberts, John F. SeymourAbstract:Highly active BTK inhibitors (BTKis) and the BCL2 inhibitor Venetoclax have transformed the therapeutic landscape for chronic lymphocytic leukemia (CLL). Results of prospective clinical trials demonstrate the efficacy of Venetoclax to salvage patients with disease progression on BTKis, but data on BTKi therapy after disease progression on Venetoclax are limited, especially regarding durability of benefit. We retrospectively evaluated the records of 23 consecutive patients with relapsed/refractory CLL who received a BTKi (ibrutinib, n = 21; zanubrutinib, n = 2) after stopping Venetoclax because of progressive disease. Median progression-free survival (PFS) and median overall survival after BTKi initiation were 34 months (range,
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fixed duration of Venetoclax rituximab in relapsed refractory chronic lymphocytic leukemia eradicates minimal residual disease and prolongs survival post treatment follow up of the murano phase iii study
Journal of Clinical Oncology, 2019Co-Authors: A P Kater, John F. Seymour, Barbara Eichhorst, Peter Hillmen, Carolyn Owen, Anton W Langerak, Maria Verdugo, Jenny Wu, Elizabeth Punnoose, Yanwen JiangAbstract:PURPOSE: The MURANO study demonstrated significant progression-free survival (PFS) benefit for fixed-duration Venetoclax-rituximab compared with bendamustine-rituximab in relapsed/refractory chronic lymphocytic leukemia. With all patients off treatment, we report minimal residual disease (MRD) kinetics and updated outcomes. METHODS: Patients were randomly assigned to 2 years of Venetoclax plus rituximab during the first six cycles, or six cycles of bendamustine-rituximab. Primary end point was PFS. Safety and peripheral blood (PB) MRD status-at cycle 4, 2 to 3 months after end of combination therapy (EOCT), and every 3 to 6 months thereafter-were secondary end points. RESULTS: Of 194 patients, 174 (90%) completed the Venetoclax-rituximab phase and 130 (67%) completed 2 years of Venetoclax. With a median follow-up of 36 months, PFS and overall survival remain superior to bendamustine-rituximab (hazard ratio, 0.16 [95% CI, 0.12 to 0.23]; and hazard ratio, 0.50 [95% CI, 0.30 to 0.85], respectively). Patients who received Venetoclax-rituximab achieved a higher rate of PB undetectable MRD (uMRD; less than 10-4) at EOCT (62% v 13%) with superiority sustained through month 24 (end of therapy). Overall, uMRD status at EOCT predicted longer PFS. Among those with detectable MRD, low-level MRD (10-4 to less than 10-2) predicted improved PFS compared with high-level MRD (10-2 or greater). At a median of 9.9 months (range, 1.4 to 22.5 months) after completing fixed-duration Venetoclax-rituximab, overall only 12% (16 of 130) of patients developed disease progression (11 high-level MRD, three low-level MRD). At the end of therapy, 70% and 98% of patients with uMRD remained in uMRD and without disease progression, respectively. CONCLUSION: With all patients having finished treatment, continued benefit was observed for Venetoclax-rituximab compared with bendamustine-rituximab. uMRD rates were durable and predicted longer PFS, which establishes the impact of PB MRD on the benefit of fixed-duration, Venetoclax-containing treatment. Low conversion to detectable MRD and sustained PFS after completion of 2 years of Venetoclax-rituximab demonstrate the feasibility of this regimen.
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fixed duration of Venetoclax rituximab in relapsed refractory chronic lymphocytic leukemia eradicates minimal residual disease and prolongs survival post treatment follow up of the murano phase iii study
Journal of Clinical Oncology, 2019Co-Authors: Arnon P. Kater, John F. Seymour, Barbara Eichhorst, Peter Hillmen, Carolyn Owen, Anton W Langerak, Maria Verdugo, Elizabeth Punnoose, Yanwen Jiang, Jue WangAbstract:PurposeThe MURANO study demonstrated significant progression-free survival (PFS) benefit for fixed-duration Venetoclax-rituximab compared with bendamustine-rituximab in relapsed/refractory chronic lymphocytic leukemia. With all patients off treatment, we report minimal residual disease (MRD) kinetics and updated outcomes.MethodsPatients were randomly assigned to 2 years of Venetoclax plus rituximab during the first six cycles, or six cycles of bendamustine-rituximab. Primary end point was PFS. Safety and peripheral blood (PB) MRD status—at cycle 4, 2 to 3 months after end of combination therapy (EOCT), and every 3 to 6 months thereafter—were secondary end points.ResultsOf 194 patients, 174 (90%) completed the Venetoclax-rituximab phase and 130 (67%) completed 2 years of Venetoclax. With a median follow-up of 36 months, PFS and overall survival remain superior to bendamustine-rituximab (hazard ratio, 0.16 [95% CI, 0.12 to 0.23]; and hazard ratio, 0.50 [95% CI, 0.30 to 0.85], respectively). Patients who rec...
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Fixed Duration of Venetoclax-Rituximab in Relapsed/Refractory Chronic Lymphocytic Leukemia Eradicates Minimal Residual Disease and Prolongs Survival: Post-Treatment Follow-Up of the MURANO Phase III Study
Journal of Clinical Oncology, 2018Co-Authors: Arnon P. Kater, John F. Seymour, Barbara Eichhorst, Peter Hillmen, Carolyn Owen, Anton W Langerak, Maria Verdugo, Jenny Wu, Elizabeth Punnoose, Yanwen JiangAbstract:PurposeThe MURANO study demonstrated significant progression-free survival (PFS) benefit for fixed-duration Venetoclax-rituximab compared with bendamustine-rituximab in relapsed/refractory chronic lymphocytic leukemia. With all patients off treatment, we report minimal residual disease (MRD) kinetics and updated outcomes.MethodsPatients were randomly assigned to 2 years of Venetoclax plus rituximab during the first six cycles, or six cycles of bendamustine-rituximab. Primary end point was PFS. Safety and peripheral blood (PB) MRD status—at cycle 4, 2 to 3 months after end of combination therapy (EOCT), and every 3 to 6 months thereafter—were secondary end points.ResultsOf 194 patients, 174 (90%) completed the Venetoclax-rituximab phase and 130 (67%) completed 2 years of Venetoclax. With a median follow-up of 36 months, PFS and overall survival remain superior to bendamustine-rituximab (hazard ratio, 0.16 [95% CI, 0.12 to 0.23]; and hazard ratio, 0.50 [95% CI, 0.30 to 0.85], respectively). Patients who rec...
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Venetoclax–Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia
The New England journal of medicine, 2018Co-Authors: John F. Seymour, Thomas J. Kipps, Barbara Eichhorst, Peter Hillmen, James D'rozario, Sarit Assouline, Carolyn Owen, John F. Gerecitano, Tadeusz Robak, Javier De La SernaAbstract:Abstract Background Venetoclax inhibits BCL2, an antiapoptotic protein that is pathologically overexpressed and that is central to the survival of chronic lymphocytic leukemia cells. We evaluated the efficacy of Venetoclax in combination with rituximab in patients with relapsed or refractory chronic lymphocytic leukemia. Methods In this randomized, open-label, phase 3 trial, we randomly assigned 389 patients to receive Venetoclax for up to 2 years (from day 1 of cycle 1) plus rituximab for the first 6 months (Venetoclax–rituximab group) or bendamustine plus rituximab for 6 months (bendamustine–rituximab group). The trial design did not include crossover to Venetoclax plus rituximab for patients in the bendamustine–rituximab group in whom progression occurred. The primary end point was investigator-assessed progression-free survival. Results After a median follow-up period of 23.8 months, the rate of investigator-assessed progression-free survival was significantly higher in the Venetoclax–rituximab group ...
Peter Hillmen - One of the best experts on this subject based on the ideXlab platform.
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phase 1b study of Venetoclax obinutuzumab in previously untreated and relapsed refractory chronic lymphocytic leukemia
Blood, 2019Co-Authors: Ian W Flinn, Peter Hillmen, Jg Gribben, W Wierda, Martin J S Dyer, Michael Maris, Richard R Furman, Kerry A Rogers, Swaminathan P Iyer, Anne QuilletmaryAbstract:This single-arm, open-label, phase 1b study evaluated the maximum tolerated dose (MTD) of Venetoclax when given with obinutuzumab and its safety and tolerability in patients with relapsed/refractory (R/R) or previously untreated (first line [1L]) chronic lymphocytic leukemia (CLL). Venetoclax dose initially was escalated (100-400 mg) in a 3 + 3 design to define MTD combined with standard-dose obinutuzumab. Patients received Venetoclax (schedule A) or obinutuzumab (schedule B) first to compare safety and determine dose/schedule for expansion. Venetoclax-obinutuzumab was administered for 6 cycles, followed by Venetoclax monotherapy until disease progression (R/R) or fixed duration 1-year treatment (1L). Fifty R/R and 32 1L patients were enrolled. No dose-limiting toxicities were observed. Safety, including incidence of tumor lysis syndrome (TLS), did not differ between schedules (2 laboratory TLSs per schedule). Schedule B and a 400-mg dose of Venetoclax were chosen for expansion. The most common grade 3-4 adverse event was neutropenia (R/R, 58% of patients; 1L, 53%). Rates of grade 3-4 infections were 29% (R/R) and 13% (1L); no fatal infections occurred in 1L. All infusion-related reactions were grade 1-2, except for 2 grade 3 events. No clinical TLS was observed. Overall best response rate was 95% in R/R (complete response [CR]/CR with incomplete marrow recovery [CRi], 37%) and 100% in 1L (CR/CRi, 78%) patients. Rate of undetectable (<10−4) minimal residual disease (uMRD) in peripheral blood for R/R and 1L patients, respectively, was 64% and 91% ≥3 months after last obinutuzumab dose. Venetoclax and obinutuzumab therapy had an acceptable safety profile and elicited durable responses and high rates of uMRD. This trial was registered at www.clinicaltrials.gov as #{"type":"clinical-trial","attrs":{"text":"NCT01685892","term_id":"NCT01685892"}}NCT01685892.
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fixed duration of Venetoclax rituximab in relapsed refractory chronic lymphocytic leukemia eradicates minimal residual disease and prolongs survival post treatment follow up of the murano phase iii study
Journal of Clinical Oncology, 2019Co-Authors: A P Kater, John F. Seymour, Barbara Eichhorst, Peter Hillmen, Carolyn Owen, Anton W Langerak, Maria Verdugo, Jenny Wu, Elizabeth Punnoose, Yanwen JiangAbstract:PURPOSE: The MURANO study demonstrated significant progression-free survival (PFS) benefit for fixed-duration Venetoclax-rituximab compared with bendamustine-rituximab in relapsed/refractory chronic lymphocytic leukemia. With all patients off treatment, we report minimal residual disease (MRD) kinetics and updated outcomes. METHODS: Patients were randomly assigned to 2 years of Venetoclax plus rituximab during the first six cycles, or six cycles of bendamustine-rituximab. Primary end point was PFS. Safety and peripheral blood (PB) MRD status-at cycle 4, 2 to 3 months after end of combination therapy (EOCT), and every 3 to 6 months thereafter-were secondary end points. RESULTS: Of 194 patients, 174 (90%) completed the Venetoclax-rituximab phase and 130 (67%) completed 2 years of Venetoclax. With a median follow-up of 36 months, PFS and overall survival remain superior to bendamustine-rituximab (hazard ratio, 0.16 [95% CI, 0.12 to 0.23]; and hazard ratio, 0.50 [95% CI, 0.30 to 0.85], respectively). Patients who received Venetoclax-rituximab achieved a higher rate of PB undetectable MRD (uMRD; less than 10-4) at EOCT (62% v 13%) with superiority sustained through month 24 (end of therapy). Overall, uMRD status at EOCT predicted longer PFS. Among those with detectable MRD, low-level MRD (10-4 to less than 10-2) predicted improved PFS compared with high-level MRD (10-2 or greater). At a median of 9.9 months (range, 1.4 to 22.5 months) after completing fixed-duration Venetoclax-rituximab, overall only 12% (16 of 130) of patients developed disease progression (11 high-level MRD, three low-level MRD). At the end of therapy, 70% and 98% of patients with uMRD remained in uMRD and without disease progression, respectively. CONCLUSION: With all patients having finished treatment, continued benefit was observed for Venetoclax-rituximab compared with bendamustine-rituximab. uMRD rates were durable and predicted longer PFS, which establishes the impact of PB MRD on the benefit of fixed-duration, Venetoclax-containing treatment. Low conversion to detectable MRD and sustained PFS after completion of 2 years of Venetoclax-rituximab demonstrate the feasibility of this regimen.
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fixed duration of Venetoclax rituximab in relapsed refractory chronic lymphocytic leukemia eradicates minimal residual disease and prolongs survival post treatment follow up of the murano phase iii study
Journal of Clinical Oncology, 2019Co-Authors: Arnon P. Kater, John F. Seymour, Barbara Eichhorst, Peter Hillmen, Carolyn Owen, Anton W Langerak, Maria Verdugo, Elizabeth Punnoose, Yanwen Jiang, Jue WangAbstract:PurposeThe MURANO study demonstrated significant progression-free survival (PFS) benefit for fixed-duration Venetoclax-rituximab compared with bendamustine-rituximab in relapsed/refractory chronic lymphocytic leukemia. With all patients off treatment, we report minimal residual disease (MRD) kinetics and updated outcomes.MethodsPatients were randomly assigned to 2 years of Venetoclax plus rituximab during the first six cycles, or six cycles of bendamustine-rituximab. Primary end point was PFS. Safety and peripheral blood (PB) MRD status—at cycle 4, 2 to 3 months after end of combination therapy (EOCT), and every 3 to 6 months thereafter—were secondary end points.ResultsOf 194 patients, 174 (90%) completed the Venetoclax-rituximab phase and 130 (67%) completed 2 years of Venetoclax. With a median follow-up of 36 months, PFS and overall survival remain superior to bendamustine-rituximab (hazard ratio, 0.16 [95% CI, 0.12 to 0.23]; and hazard ratio, 0.50 [95% CI, 0.30 to 0.85], respectively). Patients who rec...
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Fixed Duration of Venetoclax-Rituximab in Relapsed/Refractory Chronic Lymphocytic Leukemia Eradicates Minimal Residual Disease and Prolongs Survival: Post-Treatment Follow-Up of the MURANO Phase III Study
Journal of Clinical Oncology, 2018Co-Authors: Arnon P. Kater, John F. Seymour, Barbara Eichhorst, Peter Hillmen, Carolyn Owen, Anton W Langerak, Maria Verdugo, Jenny Wu, Elizabeth Punnoose, Yanwen JiangAbstract:PurposeThe MURANO study demonstrated significant progression-free survival (PFS) benefit for fixed-duration Venetoclax-rituximab compared with bendamustine-rituximab in relapsed/refractory chronic lymphocytic leukemia. With all patients off treatment, we report minimal residual disease (MRD) kinetics and updated outcomes.MethodsPatients were randomly assigned to 2 years of Venetoclax plus rituximab during the first six cycles, or six cycles of bendamustine-rituximab. Primary end point was PFS. Safety and peripheral blood (PB) MRD status—at cycle 4, 2 to 3 months after end of combination therapy (EOCT), and every 3 to 6 months thereafter—were secondary end points.ResultsOf 194 patients, 174 (90%) completed the Venetoclax-rituximab phase and 130 (67%) completed 2 years of Venetoclax. With a median follow-up of 36 months, PFS and overall survival remain superior to bendamustine-rituximab (hazard ratio, 0.16 [95% CI, 0.12 to 0.23]; and hazard ratio, 0.50 [95% CI, 0.30 to 0.85], respectively). Patients who rec...
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Venetoclax–Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia
The New England journal of medicine, 2018Co-Authors: John F. Seymour, Thomas J. Kipps, Barbara Eichhorst, Peter Hillmen, James D'rozario, Sarit Assouline, Carolyn Owen, John F. Gerecitano, Tadeusz Robak, Javier De La SernaAbstract:Abstract Background Venetoclax inhibits BCL2, an antiapoptotic protein that is pathologically overexpressed and that is central to the survival of chronic lymphocytic leukemia cells. We evaluated the efficacy of Venetoclax in combination with rituximab in patients with relapsed or refractory chronic lymphocytic leukemia. Methods In this randomized, open-label, phase 3 trial, we randomly assigned 389 patients to receive Venetoclax for up to 2 years (from day 1 of cycle 1) plus rituximab for the first 6 months (Venetoclax–rituximab group) or bendamustine plus rituximab for 6 months (bendamustine–rituximab group). The trial design did not include crossover to Venetoclax plus rituximab for patients in the bendamustine–rituximab group in whom progression occurred. The primary end point was investigator-assessed progression-free survival. Results After a median follow-up period of 23.8 months, the rate of investigator-assessed progression-free survival was significantly higher in the Venetoclax–rituximab group ...
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fixed duration of Venetoclax rituximab in relapsed refractory chronic lymphocytic leukemia eradicates minimal residual disease and prolongs survival post treatment follow up of the murano phase iii study
Journal of Clinical Oncology, 2019Co-Authors: A P Kater, John F. Seymour, Barbara Eichhorst, Peter Hillmen, Carolyn Owen, Anton W Langerak, Maria Verdugo, Jenny Wu, Elizabeth Punnoose, Yanwen JiangAbstract:PURPOSE: The MURANO study demonstrated significant progression-free survival (PFS) benefit for fixed-duration Venetoclax-rituximab compared with bendamustine-rituximab in relapsed/refractory chronic lymphocytic leukemia. With all patients off treatment, we report minimal residual disease (MRD) kinetics and updated outcomes. METHODS: Patients were randomly assigned to 2 years of Venetoclax plus rituximab during the first six cycles, or six cycles of bendamustine-rituximab. Primary end point was PFS. Safety and peripheral blood (PB) MRD status-at cycle 4, 2 to 3 months after end of combination therapy (EOCT), and every 3 to 6 months thereafter-were secondary end points. RESULTS: Of 194 patients, 174 (90%) completed the Venetoclax-rituximab phase and 130 (67%) completed 2 years of Venetoclax. With a median follow-up of 36 months, PFS and overall survival remain superior to bendamustine-rituximab (hazard ratio, 0.16 [95% CI, 0.12 to 0.23]; and hazard ratio, 0.50 [95% CI, 0.30 to 0.85], respectively). Patients who received Venetoclax-rituximab achieved a higher rate of PB undetectable MRD (uMRD; less than 10-4) at EOCT (62% v 13%) with superiority sustained through month 24 (end of therapy). Overall, uMRD status at EOCT predicted longer PFS. Among those with detectable MRD, low-level MRD (10-4 to less than 10-2) predicted improved PFS compared with high-level MRD (10-2 or greater). At a median of 9.9 months (range, 1.4 to 22.5 months) after completing fixed-duration Venetoclax-rituximab, overall only 12% (16 of 130) of patients developed disease progression (11 high-level MRD, three low-level MRD). At the end of therapy, 70% and 98% of patients with uMRD remained in uMRD and without disease progression, respectively. CONCLUSION: With all patients having finished treatment, continued benefit was observed for Venetoclax-rituximab compared with bendamustine-rituximab. uMRD rates were durable and predicted longer PFS, which establishes the impact of PB MRD on the benefit of fixed-duration, Venetoclax-containing treatment. Low conversion to detectable MRD and sustained PFS after completion of 2 years of Venetoclax-rituximab demonstrate the feasibility of this regimen.
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fixed duration of Venetoclax rituximab in relapsed refractory chronic lymphocytic leukemia eradicates minimal residual disease and prolongs survival post treatment follow up of the murano phase iii study
Journal of Clinical Oncology, 2019Co-Authors: Arnon P. Kater, John F. Seymour, Barbara Eichhorst, Peter Hillmen, Carolyn Owen, Anton W Langerak, Maria Verdugo, Elizabeth Punnoose, Yanwen Jiang, Jue WangAbstract:PurposeThe MURANO study demonstrated significant progression-free survival (PFS) benefit for fixed-duration Venetoclax-rituximab compared with bendamustine-rituximab in relapsed/refractory chronic lymphocytic leukemia. With all patients off treatment, we report minimal residual disease (MRD) kinetics and updated outcomes.MethodsPatients were randomly assigned to 2 years of Venetoclax plus rituximab during the first six cycles, or six cycles of bendamustine-rituximab. Primary end point was PFS. Safety and peripheral blood (PB) MRD status—at cycle 4, 2 to 3 months after end of combination therapy (EOCT), and every 3 to 6 months thereafter—were secondary end points.ResultsOf 194 patients, 174 (90%) completed the Venetoclax-rituximab phase and 130 (67%) completed 2 years of Venetoclax. With a median follow-up of 36 months, PFS and overall survival remain superior to bendamustine-rituximab (hazard ratio, 0.16 [95% CI, 0.12 to 0.23]; and hazard ratio, 0.50 [95% CI, 0.30 to 0.85], respectively). Patients who rec...
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Fixed Duration of Venetoclax-Rituximab in Relapsed/Refractory Chronic Lymphocytic Leukemia Eradicates Minimal Residual Disease and Prolongs Survival: Post-Treatment Follow-Up of the MURANO Phase III Study
Journal of Clinical Oncology, 2018Co-Authors: Arnon P. Kater, John F. Seymour, Barbara Eichhorst, Peter Hillmen, Carolyn Owen, Anton W Langerak, Maria Verdugo, Jenny Wu, Elizabeth Punnoose, Yanwen JiangAbstract:PurposeThe MURANO study demonstrated significant progression-free survival (PFS) benefit for fixed-duration Venetoclax-rituximab compared with bendamustine-rituximab in relapsed/refractory chronic lymphocytic leukemia. With all patients off treatment, we report minimal residual disease (MRD) kinetics and updated outcomes.MethodsPatients were randomly assigned to 2 years of Venetoclax plus rituximab during the first six cycles, or six cycles of bendamustine-rituximab. Primary end point was PFS. Safety and peripheral blood (PB) MRD status—at cycle 4, 2 to 3 months after end of combination therapy (EOCT), and every 3 to 6 months thereafter—were secondary end points.ResultsOf 194 patients, 174 (90%) completed the Venetoclax-rituximab phase and 130 (67%) completed 2 years of Venetoclax. With a median follow-up of 36 months, PFS and overall survival remain superior to bendamustine-rituximab (hazard ratio, 0.16 [95% CI, 0.12 to 0.23]; and hazard ratio, 0.50 [95% CI, 0.30 to 0.85], respectively). Patients who rec...
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Venetoclax–Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia
The New England journal of medicine, 2018Co-Authors: John F. Seymour, Thomas J. Kipps, Barbara Eichhorst, Peter Hillmen, James D'rozario, Sarit Assouline, Carolyn Owen, John F. Gerecitano, Tadeusz Robak, Javier De La SernaAbstract:Abstract Background Venetoclax inhibits BCL2, an antiapoptotic protein that is pathologically overexpressed and that is central to the survival of chronic lymphocytic leukemia cells. We evaluated the efficacy of Venetoclax in combination with rituximab in patients with relapsed or refractory chronic lymphocytic leukemia. Methods In this randomized, open-label, phase 3 trial, we randomly assigned 389 patients to receive Venetoclax for up to 2 years (from day 1 of cycle 1) plus rituximab for the first 6 months (Venetoclax–rituximab group) or bendamustine plus rituximab for 6 months (bendamustine–rituximab group). The trial design did not include crossover to Venetoclax plus rituximab for patients in the bendamustine–rituximab group in whom progression occurred. The primary end point was investigator-assessed progression-free survival. Results After a median follow-up period of 23.8 months, the rate of investigator-assessed progression-free survival was significantly higher in the Venetoclax–rituximab group ...
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Venetoclax rituximab in relapsed or refractory chronic lymphocytic leukemia
The New England Journal of Medicine, 2018Co-Authors: John F. Seymour, Thomas J. Kipps, Barbara Eichhorst, Peter Hillmen, Sarit Assouline, Carolyn Owen, John F. Gerecitano, Tadeusz Robak, James Drozario, Javier De La SernaAbstract:Abstract Background Venetoclax inhibits BCL2, an antiapoptotic protein that is pathologically overexpressed and that is central to the survival of chronic lymphocytic leukemia cells. We evaluated the efficacy of Venetoclax in combination with rituximab in patients with relapsed or refractory chronic lymphocytic leukemia. Methods In this randomized, open-label, phase 3 trial, we randomly assigned 389 patients to receive Venetoclax for up to 2 years (from day 1 of cycle 1) plus rituximab for the first 6 months (Venetoclax–rituximab group) or bendamustine plus rituximab for 6 months (bendamustine–rituximab group). The trial design did not include crossover to Venetoclax plus rituximab for patients in the bendamustine–rituximab group in whom progression occurred. The primary end point was investigator-assessed progression-free survival. Results After a median follow-up period of 23.8 months, the rate of investigator-assessed progression-free survival was significantly higher in the Venetoclax–rituximab group ...
