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Ian W. Flinn - One of the best experts on this subject based on the ideXlab platform.
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outcomes of patients with up to 6 years of follow up from a phase 2 study of Idelalisib for relapsed indolent lymphomas
Leukemia & Lymphoma, 2021Co-Authors: Nina D Wagnerjohnston, Ian W. Flinn, Wojciech Jurczak, Gilles Salles, Christopher R Flowers, Peter Martin, Stephen J Schuster, Sven Devos, Andreas Viardot, Guan XingAbstract:The phase 2 study of Idelalisib monotherapy for indolent non-Hodgkin lymphomas (iNHLs) was completed in 2018; final efficacy and safety data with up to 6.7 years long-term follow-up are reported. P...
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Idelalisib in combination with rituximab or bendamustine or both in patients with relapsed refractory chronic lymphocytic leukemia
HemaSphere, 2018Co-Authors: Steven Coutre, Jacqueline C. Barrientos, Sven De Vos, Ian W. Flinn, Jeff P Sharman, Marshall T Schreeder, Thomas E Boyd, Nathan Fowler, Nina Wagnerjohnson, Lyndah DreilingAbstract:AbstractPhosphatidylinositol 3-kinase-delta (PI3Kδ) signaling is critical for proliferation, survival, homing, and tissue retention of malignant B cells. Idelalisib, a selective oral inhibitor of PI3Kδ, has shown considerable single-agent activity in patients with heavily pretreated chronic lymphocy
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combinations of Idelalisib with rituximab and or bendamustine in patients with recurrent indolent non hodgkin lymphoma
Blood Advances, 2016Co-Authors: Sven De Vos, Steven Coutre, Jacqueline C. Barrientos, Ian W. Flinn, Jeff P Sharman, Nina D Wagnerjohnston, Marshall T Schreeder, Nathan Fowler, Ralph V Boccia, Kanti R. RaiAbstract:Idelalisib, a first-in-class oral inhibitor of phosphatidylinositol-3-kinase δ, has shown considerable antitumor activity as a monotherapy in recurrent indolent non-Hodgkin lymphoma (iNHL). To evaluate the safety and activity of Idelalisib in combination with immunotherapy, chemotherapy, or both, 79 patients with relapsed/refractory iNHL were enrolled based on investigator preference in 3 treatment groups. Patients received continuous Idelalisib in combination with (1) rituximab (IR; 375 mg/m2 weekly × 8 doses), (2) bendamustine (IB; 90 mg/m2 per day × 2, for 6 cycles), or (3) both bendamustine and rituximab at aforementioned doses (IBR; monthly × 6 cycles). Patients had a median age of 61 years, a median of 3 prior therapies, and 46% had refractory disease. The overall response rate was 75% (22% complete response) for IR, 88% (36%) for IB, and 79% (43%) for IBR. The median progression-free survival was 37.1 months overall: 29.7 months for IR, 32.8 for IB, and 37.1 months for IBR. The median duration of response was 28.6 months in the IR group and has not been reached in the IB and IBR groups. The most common grade ≥3 adverse events and laboratory abnormalities were neutropenia (41%), pneumonia (19%), transaminase elevations (16%), diarrhea/colitis (15%), and rash (9%). The safety and efficacy reflected in these early data, however, stand in contrast with later observations of significant toxicity in subsequent phase 3 trials in frontline chronic lymphocytic leukemia and less heavily pretreated iNHL patients. Our findings highlight the limitations of phase 1 trial data in the assessment of new regimens. This trial was registered at www.clinicaltrials.gov as #NCT01088048 (an extension study was registered at www.clinicaltrials.gov as #NCT01090414).
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Management of transaminase elevations in patients receiving Idelalisib.
Journal of Clinical Oncology, 2016Co-Authors: William G Wierda, Steven Coutre, Susan O'brien, Terry Newcomb, Ian W. Flinn, Andrew D. Zelenetz, Ajay K. Gopal, Gilles Salles, Christopher C. WaldapfelAbstract:7532Background: Transaminase elevation associated with Idelalisib (IDELA) typically occurs early during treatment (median onset, 8 wk) and is often asymptomatic. Currently recommended management of...
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A phase 2 study of Idelalisib plus rituximab in treatment-naïve older patients with chronic lymphocytic leukemia
Blood, 2015Co-Authors: Susan O'brien, Michael J Keating, Nicole Lamanna, Thomas J. Kipps, Ian W. Flinn, Andrew D. Zelenetz, Jan A. Burger, Siddhartha Mitra, Leanne HolesAbstract:Idelalisib is a first-in-class oral inhibitor of PI3Kδ that has shown substantial activity in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). To evaluate Idelalisib as initial therapy, 64 treatment-naive older patients with CLL or small lymphocytic leukemia (median age, 71 years; range, 65-90) were treated with rituximab 375 mg/m2 weekly ×8 and Idelalisib 150 mg twice daily continuously for 48 weeks. Patients completing 48 weeks without progression could continue to receive Idelalisib on an extension study. The median time on treatment was 22.4 months (range, 0.8-45.8+). The overall response rate (ORR) was 97%, including 19% complete responses. The ORR was 100% in patients with del(17p)/TP53 mutations and 97% in those with unmutated IGHV. Progression-free survival was 83% at 36 months. The most frequent (>30%) adverse events (any grade) were diarrhea (including colitis) (64%), rash (58%), pyrexia (42%), nausea (38%), chills (36%), cough (33%), and fatigue (31%). Elevated alanine transaminase/aspartate transaminase was seen in 67% of patients (23% grade ≥3). The combination of Idelalisib and rituximab was highly active, resulting in durable disease control in treatment-naive older patients with CLL. These results support the further development of Idelalisib as initial treatment of CLL. This study is registered at ClinicalTrials.gov as #NCT01203930.
Nina D Wagnerjohnston - One of the best experts on this subject based on the ideXlab platform.
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Idelalisib immune related toxicity is associated with improved treatment response
Leukemia & Lymphoma, 2021Co-Authors: Nina D Wagnerjohnston, Tadeusz Robak, Jennifer R Brown, Richard R. Furman, Nishanthan Rajakumaraswamy, Jeff P Sharman, Rebecca J Chan, Guan Xing, Gilles Salles, Ajay K. GopalAbstract:Idelalisib is associated with increased occurrence of immune-related adverse events (irAEs). Clinical observations suggest a correlation between immune checkpoint inhibitor-induced irAEs and survival outcomes in patients with solid tumors; however, this relationship in hematologic malignancies is not well understood. In a post hoc analysis of 3 registrational trials, we explored the relationship between Grade ≥3 diarrhea/colitis and alanine/aspartate transaminase (ALT/AST) elevation incidences and efficacy endpoints in patients with indolent non-Hodgkin lymphoma (iNHL), follicular lymphoma (FL), and chronic lymphocytic leukemia treated with Idelalisib. Grade ≥3 diarrhea/colitis was associated with higher overall response rate (ORR) and longer progression-free survival (PFS) for all subgroups. Grade ≥3 ALT/AST elevations were associated with improved duration of response and overall survival for all subgroups and improved ORR and PFS for patients with FL or iNHL. Our analysis in hematologic malignancies showed a trend correlating Idelalisib-induced Grade ≥3 irAEs with improved efficacy.
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retrospective analysis of the impact of adverse event triggered Idelalisib interruption and dose reduction on clinical outcomes in patients with relapsed refractory b cell malignancies
Clinical Lymphoma Myeloma & Leukemia, 2021Co-Authors: Rebecca J Chan, Nishanthan Rajakumaraswamy, Guan Xing, Bianca Ruzicka, Nina D WagnerjohnstonAbstract:Abstract Background Idelalisib is a phosphatidylinositol 3-kinase δ inhibitor approved for relapsed/refractory follicular lymphoma, a type of indolent non-Hodgkin lymphoma (iNHL), and chronic lymphocytic leukemia (CLL). Idelalisib-triggered adverse events (AEs) may be managed with treatment interruption and/or dose reduction, potentially extending therapy duration and increasing the likelihood of continued response. Patients and Methods Post hoc analyses were conducted to evaluate clinical outcomes after AE-induced Idelalisib interruption for 125 patients with iNHL and 283 with CLL. Results Progression-free survival (PFS) was longer for patients with iNHL who experienced ≥ 2 interruptions versus those with 0 interruptions who discontinued Idelalisib or study because of AEs (hazard ratio 0.33; P = .0212). Both PFS and overall survival were longer for patients with CLL with ≥ 2 interruptions versus 0 interruptions in those who discontinued therapy because of an AE (hazard ratio PFS 0.50, overall survival 0.41; P Conclusion Idelalisib interruption and dose reduction were associated with enhanced clinical outcomes for patients with relapsed/refractory iNHL or CLL who experienced an AE, supporting this management strategy when indicated.
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outcomes of patients with up to 6 years of follow up from a phase 2 study of Idelalisib for relapsed indolent lymphomas
Leukemia & Lymphoma, 2021Co-Authors: Nina D Wagnerjohnston, Ian W. Flinn, Wojciech Jurczak, Gilles Salles, Christopher R Flowers, Peter Martin, Stephen J Schuster, Sven Devos, Andreas Viardot, Guan XingAbstract:The phase 2 study of Idelalisib monotherapy for indolent non-Hodgkin lymphomas (iNHLs) was completed in 2018; final efficacy and safety data with up to 6.7 years long-term follow-up are reported. P...
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safety and tolerability of Idelalisib lenalidomide and rituximab in relapsed and refractory lymphoma the alliance for clinical trials in oncology a051201 and a051202 phase 1 trials
The Lancet Haematology, 2017Co-Authors: Nina D Wagnerjohnston, Brandelyn N Pitcher, Sinho Jung, Nancy L Bartlett, Steven I Park, Kristy L Richards, Amanda F Cashen, Anthony Jaslowski, Sonali M Smith, Steven I Park, Anthony Jaslowski, Scott E SmithAbstract:Summary Background A new generation of biological and targeted agents might potentially replace traditional cytotoxic agents in lymphoma. Lenalidomide plus rituximab was felt to be a safe and promising backbone based on available data. Idelalisib is an oral phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor that has promising activity as a monotherapy in refractory indolent lymphomas. The primary objective of these two trials was to determine the maximum tolerated dose of lenalidomide in combination with rituximab and Idelalisib in relapsed follicular and mantle cell lymphoma. Methods A051201 (mantle cell lymphoma) and A051202 (follicular lymphoma) were phase 1 trials. Patients with histologically documented relapsed mantle cell lymphoma who had not received previous lenalidomide or Idelalisib (A051201) were started with oral lenalidomide 15 mg on days 1–21 in a 28 day cycle, oral Idelalisib 150 mg twice a day with continuous 28-day cycles, and intravenous rituximab 375 mg/m 2 weekly during cycle 1. Patients with histologically documented relapsed follicular lymphoma and time to progression 6 months or longer from last rituximab-containing regimen (A051202) were started with oral lenalidomide 10 mg on days 1–21 every 28 days and oral Idelalisib 150 mg twice a day with continuous 28-day cycles, and intravenous rituximab 375 mg/m 2 on cycle 1, day 8, day 15, day 22, and cycle 2, day 1. The primary endpoints of the studies were safety and tolerability of combining Idelalisib with lenalidomide and rituximab in patients with relapsed mantle cell lymphoma (A051201) and relapsed follicular lymphoma (A051202). All analyses were by intention to treat. The trials were registered at ClinicalTrials.gov, number NCT01838434 (A051201) and number NCT01644799 (A051202). Findings Between July 9, 2013, and Sept 30, 2014, 11 patients (three with mantle cell lymphoma and eight with follicular lymphoma) were enrolled. Among the first eight patients, four experienced unexpected dose-limiting toxicities: grade 4 sepsis syndrome, grade 4 hypotension with grade 3 rash and fevers, grade 4 aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation with fevers, and grade 3 pulmonary infection with grade 3 maculopapular rash. Symptom onset was 9–20 days after treatment initiation, coinciding with rituximab infusions. Both studies were amended to remove rituximab, but two of three additional patients had grade 3 rashes and one had grade 3 AST elevation. Both trials were permanently closed. The most common grade 3–4 adverse events were ALT elevation (two [67%] of three) and rash (two [67%] of three) for patients with mantle cell lymphoma and neutropenia (five [63%] of eight) and rash (four [50%] of eight) for patients with follicular lymphoma. The primary endpoint of safety and tolerability was not met. Interpretation The combination of Idelalisib, lenalidomide, and rituximab in these trials is excessively toxic, and these trials serve as cautionary notes as new combinations are proposed. Off-target effects, drug–drug interactions, and emerging toxicities should be carefully assessed when investigating biological agents in combination and should never be done outside of a clinical trial setting. Funding National Cancer Institute of the National Institutes of Health.
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combinations of Idelalisib with rituximab and or bendamustine in patients with recurrent indolent non hodgkin lymphoma
Blood Advances, 2016Co-Authors: Sven De Vos, Steven Coutre, Jacqueline C. Barrientos, Ian W. Flinn, Jeff P Sharman, Nina D Wagnerjohnston, Marshall T Schreeder, Nathan Fowler, Ralph V Boccia, Kanti R. RaiAbstract:Idelalisib, a first-in-class oral inhibitor of phosphatidylinositol-3-kinase δ, has shown considerable antitumor activity as a monotherapy in recurrent indolent non-Hodgkin lymphoma (iNHL). To evaluate the safety and activity of Idelalisib in combination with immunotherapy, chemotherapy, or both, 79 patients with relapsed/refractory iNHL were enrolled based on investigator preference in 3 treatment groups. Patients received continuous Idelalisib in combination with (1) rituximab (IR; 375 mg/m2 weekly × 8 doses), (2) bendamustine (IB; 90 mg/m2 per day × 2, for 6 cycles), or (3) both bendamustine and rituximab at aforementioned doses (IBR; monthly × 6 cycles). Patients had a median age of 61 years, a median of 3 prior therapies, and 46% had refractory disease. The overall response rate was 75% (22% complete response) for IR, 88% (36%) for IB, and 79% (43%) for IBR. The median progression-free survival was 37.1 months overall: 29.7 months for IR, 32.8 for IB, and 37.1 months for IBR. The median duration of response was 28.6 months in the IR group and has not been reached in the IB and IBR groups. The most common grade ≥3 adverse events and laboratory abnormalities were neutropenia (41%), pneumonia (19%), transaminase elevations (16%), diarrhea/colitis (15%), and rash (9%). The safety and efficacy reflected in these early data, however, stand in contrast with later observations of significant toxicity in subsequent phase 3 trials in frontline chronic lymphocytic leukemia and less heavily pretreated iNHL patients. Our findings highlight the limitations of phase 1 trial data in the assessment of new regimens. This trial was registered at www.clinicaltrials.gov as #NCT01088048 (an extension study was registered at www.clinicaltrials.gov as #NCT01090414).
Jacqueline C. Barrientos - One of the best experts on this subject based on the ideXlab platform.
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Idelalisib in combination with rituximab or bendamustine or both in patients with relapsed refractory chronic lymphocytic leukemia
HemaSphere, 2018Co-Authors: Steven Coutre, Jacqueline C. Barrientos, Sven De Vos, Ian W. Flinn, Jeff P Sharman, Marshall T Schreeder, Thomas E Boyd, Nathan Fowler, Nina Wagnerjohnson, Lyndah DreilingAbstract:AbstractPhosphatidylinositol 3-kinase-delta (PI3Kδ) signaling is critical for proliferation, survival, homing, and tissue retention of malignant B cells. Idelalisib, a selective oral inhibitor of PI3Kδ, has shown considerable single-agent activity in patients with heavily pretreated chronic lymphocy
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Idelalisib or placebo in combination with bendamustine and rituximab in patients with relapsed or refractory chronic lymphocytic leukaemia interim results from a phase 3 randomised double blind placebo controlled trial
Lancet Oncology, 2017Co-Authors: Andrew D. Zelenetz, Jacqueline C. Barrientos, Arpad Illes, Miklos Egyed, Julio Delgado, Wojciech Jurczak, Paolo Ghia, Bertrand Coiffier, Paula MarltonAbstract:Summary Background Bendamustine plus rituximab is a standard of care for the management of patients with relapsed or refractory chronic lymphocytic leukaemia. New therapies are needed to improve clinically relevant outcomes in these patients. We assessed the efficacy and safety of adding Idelalisib, a first-in-class targeted phosphoinositide-3-kinase δ inhibitor, to bendamustine plus rituximab in this population. Methods For this international, multicentre, double-blind, placebo-controlled trial, adult patients (≥18 years) with relapsed or refractory chronic lymphocytic leukaemia requiring treatment who had measurable lymphadenopathy by CT or MRI and disease progression within 36 months since their last previous therapy were enrolled. Patients were randomly assigned (1:1) by a central interactive web response system to receive bendamustine plus rituximab for a maximum of six cycles (bendamustine: 70 mg/m 2 intravenously on days 1 and 2 for six 28-day cycles; rituximab: 375 mg/m 2 on day 1 of cycle 1, and 500 mg/m 2 on day 1 of cycles 2–6) in addition to either twice-daily oral Idelalisib (150 mg) or placebo until disease progression or intolerable study drug-related toxicity. Randomisation was stratified by high-risk features ( IGHV , del[17p], or TP53 mutation) and refractory versus relapsed disease. The primary endpoint was progression-free survival assessed by an independent review committee in the intention-to-treat population. This trial is ongoing and is registered with ClinicalTrials.gov, number NCT01569295. Findings Between June 26, 2012, and Aug 21, 2014, 416 patients were enrolled and randomly assigned to the Idelalisib (n=207) and placebo (n=209) groups. At a median follow-up of 14 months (IQR 7–18), median progression-free survival was 20·8 months (95% CI 16·6–26·4) in the Idelalisib group and 11·1 months (8·9–11·1) in the placebo group (hazard ratio [HR] 0·33, 95% CI 0·25–0·44; p vs 52 [25%] of 209). Serious adverse events, including febrile neutropenia, pneumonia, and pyrexia, were more common in the Idelalisib group (140 [68%] of 207 patients) than in the placebo group (92 [44%] of 209). Treatment-emergent adverse events leading to death occurred in 23 (11%) patients in the Idelalisib group and 15 (7%) in the placebo group, including six deaths from infections in the Idelalisib group and three from infections in the placebo group. Interpretation Idelalisib in combination with bendamustine plus rituximab improved progression-free survival compared with bendamustine plus rituximab alone in patients with relapsed or refractory chronic lymphocytic leukaemia. However, careful attention needs to be paid to management of serious adverse events and infections associated with this regimen during treatment selection. Funding Gilead Sciences Inc.
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combinations of Idelalisib with rituximab and or bendamustine in patients with recurrent indolent non hodgkin lymphoma
Blood Advances, 2016Co-Authors: Sven De Vos, Steven Coutre, Jacqueline C. Barrientos, Ian W. Flinn, Jeff P Sharman, Nina D Wagnerjohnston, Marshall T Schreeder, Nathan Fowler, Ralph V Boccia, Kanti R. RaiAbstract:Idelalisib, a first-in-class oral inhibitor of phosphatidylinositol-3-kinase δ, has shown considerable antitumor activity as a monotherapy in recurrent indolent non-Hodgkin lymphoma (iNHL). To evaluate the safety and activity of Idelalisib in combination with immunotherapy, chemotherapy, or both, 79 patients with relapsed/refractory iNHL were enrolled based on investigator preference in 3 treatment groups. Patients received continuous Idelalisib in combination with (1) rituximab (IR; 375 mg/m2 weekly × 8 doses), (2) bendamustine (IB; 90 mg/m2 per day × 2, for 6 cycles), or (3) both bendamustine and rituximab at aforementioned doses (IBR; monthly × 6 cycles). Patients had a median age of 61 years, a median of 3 prior therapies, and 46% had refractory disease. The overall response rate was 75% (22% complete response) for IR, 88% (36%) for IB, and 79% (43%) for IBR. The median progression-free survival was 37.1 months overall: 29.7 months for IR, 32.8 for IB, and 37.1 months for IBR. The median duration of response was 28.6 months in the IR group and has not been reached in the IB and IBR groups. The most common grade ≥3 adverse events and laboratory abnormalities were neutropenia (41%), pneumonia (19%), transaminase elevations (16%), diarrhea/colitis (15%), and rash (9%). The safety and efficacy reflected in these early data, however, stand in contrast with later observations of significant toxicity in subsequent phase 3 trials in frontline chronic lymphocytic leukemia and less heavily pretreated iNHL patients. Our findings highlight the limitations of phase 1 trial data in the assessment of new regimens. This trial was registered at www.clinicaltrials.gov as #NCT01088048 (an extension study was registered at www.clinicaltrials.gov as #NCT01090414).
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Outcomes of Patients with Chronic Lymphocytic Leukemia (CLL) after Idelalisib Therapy Discontinuation
Blood, 2015Co-Authors: Jacqueline C. Barrientos, Nancy Driscoll, Manmeen Kaur, Alexis Mark, Jaewon Chung, Alison Bender, Kanti R. RaiAbstract:Objective Idelalisib is a first-in-class oral PI3Kd inhibitor approved for use in combination with rituximab in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL). We describe the characteristics, causes of discontinuation, and outcomes in patients who discontinued treatment after Idelalisib therapy. Methods 38 R/R CLL patients participated in 5 Idelalisib combination trials at the North Shore-LIJ Cancer Institute and were included in this analysis. The patients were enrolled from 2011 until 2014, and data were locked in March 1 st , 2015. Patients were evaluated for time to therapy discontinuation and reasons for discontinuation. The majority of the patients had been heavily pretreated and 39% of the patients had a high risk prognostic marker including deletion of 11q or 17p. 21 R/R CLL patients participated in the Phase Ib trial of Idelalisib in combination with several agents including Rituximab (R), Bendamustine (B) ± R, Fludarabine, Chlorambucil ± R, and Ofatumumab. The trial was designed for 48 weeks and patients were allowed to continue on an extension trial with Idelalisib if still deriving benefit. Patients on the parent trial were on therapy a median of 335 days. 42% (11/21) continued in the extension trial at the end of the parent trial. Causes of discontinuation from initial 48-week trial included: grade 4 transaminitis (1) on day 64 with failed rechallenge at lower doses; Richter9s transformation (1) on day 161; grade 3/4 diarrhea/colitis (4) on days 52, 231, 255, and 365; refractory/progressive CLL (2) on days 8 and 170; aplastic anemia (1) on day 172; and septic shock in a patient with uncontrolled autoimmune hemolytic anemia (1) on day 271. Of the patients on the extension trial, the median time on drug was 412 days with 27% (3/11) discontinuing due to grade 3/4 diarrhea/colitis; 36% (4/11) due to progression, 9% (1/11) due to pneumonia and subsequent progression 2 months later. Of the 3 patients that remain on study, their median time on therapy is 1072 days without evidence of toxicities. Of the 17 patients that participated in placebo-controlled phase III studies, 11 participated in R +/- Idelalisib (study 116) and 6 on BR+/-Idelalisib (study 115). Study 116 was unblinded during the trial: 35% (4/11) received Idelalisib + R upfront. Of these, only 2 patients (50%) were able to continue on extension study as the other 2 patients developed pneumonitis and were taken off study early. One patient is continues on study at day 1011 whereas the second patient developed progressive multifocal leukoencephalopathy on day 714 and died days after being taken off drug. 86% (6/7) of the remaining patients initially randomized to placebo crossed over to Idelalisib at the time of confirmed progression. Of these, 14% (1/6) developed both colitis and later pneumonitis, 14% (1/6) withdrew consent, and 14% (1/6) had progression of disease. For blinded study 115 (BR+/-Idelalisib), 6 patients participated: 33% (2/6) developed grade 3/4 diarrhea/colitis, 16% (1/6) developed pneumonitis, and 16% (1/6) has progressed. In our experience, none of the patients with severe diarrhea/colitis were able to maintain lower doses for a prolonged period of time without recurrent colitis or the development of pneumonitis. Since the start of these trials, 31% (12/38) of the patients have died: the overall survival after discontinuation for these patients varies widely from 0 to 303 days with a median overall survival of 64 days after discontinuation. Most patients with relapsed/refractory CLL who discontinued Idelalisib early were difficult to treat and had poor outcomes. Over the course of the trials, the Bruton9s tyrosine kinase inhibitor ibrutinib was approved and used as salvage therapy in 10 patients with confirmed progression; except for 1 patient, all patients successfully achieved a prolonged response with ibrutinib suggesting salvage therapy with a targeted agent may be a reasonable therapeutic approach for patients after Idelalisib failure. Interestingly, the rate of Richter9s transformation was extremely rare in this study (2%). Conclusions This single-institution experience with Idelalisib identifies baseline factors associated with therapy discontinuation, mainly grade 3/4 diarrhea/colitis and progression of disease as a reason for discontinuation from therapy. Our data suggest the use of ibrutinib may be a reasonable choice in patients after Idelalisib failure. Disclosures Barrientos: ASH-AMFDP: Research Funding; Gilead: Research Funding; NIH/NCATS: Research Funding. Off Label Use: Idelalisib is approved in combination with rituximab only. I will discuss our experience of Idelalisib in combination with other agents.
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safety of Idelalisib in b cell malignancies integrated analysis of eight clinical trials
Journal of Clinical Oncology, 2015Co-Authors: Steven Coutre, Jennifer R Brown, Susan Obrien, Michael J Keating, Jacqueline C. Barrientos, Sven De Vos, Richard R. Furman, John M. Pagel, Jeff P Sharman, Andrew D. ZelenetzAbstract:e18030 Background: Idelalisib (Zydelig), a first-in-class, selective, oral inhibitor of PI3Kδ, is approved in the US and EU for the treatment of chronic lymphocytic leukemia (CLL) in combination wi...
Richard R. Furman - One of the best experts on this subject based on the ideXlab platform.
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Idelalisib immune related toxicity is associated with improved treatment response
Leukemia & Lymphoma, 2021Co-Authors: Nina D Wagnerjohnston, Tadeusz Robak, Jennifer R Brown, Richard R. Furman, Nishanthan Rajakumaraswamy, Jeff P Sharman, Rebecca J Chan, Guan Xing, Gilles Salles, Ajay K. GopalAbstract:Idelalisib is associated with increased occurrence of immune-related adverse events (irAEs). Clinical observations suggest a correlation between immune checkpoint inhibitor-induced irAEs and survival outcomes in patients with solid tumors; however, this relationship in hematologic malignancies is not well understood. In a post hoc analysis of 3 registrational trials, we explored the relationship between Grade ≥3 diarrhea/colitis and alanine/aspartate transaminase (ALT/AST) elevation incidences and efficacy endpoints in patients with indolent non-Hodgkin lymphoma (iNHL), follicular lymphoma (FL), and chronic lymphocytic leukemia treated with Idelalisib. Grade ≥3 diarrhea/colitis was associated with higher overall response rate (ORR) and longer progression-free survival (PFS) for all subgroups. Grade ≥3 ALT/AST elevations were associated with improved duration of response and overall survival for all subgroups and improved ORR and PFS for patients with FL or iNHL. Our analysis in hematologic malignancies showed a trend correlating Idelalisib-induced Grade ≥3 irAEs with improved efficacy.
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Venetoclax for patients with chronic lymphocytic leukemia who progressed during or after Idelalisib therapy
Blood, 2018Co-Authors: Michael Y. Choi, Jeffrey A. Jones, Richard R. Furman, Herbert Eradat, Leonard T. Heffner, Brenda Chyla, Lang Zhou, Suresh Agarwal, Tina WaskiewiczAbstract:B-cell receptor pathway inhibitors (BCRis) have transformed treatment of chronic lymphocytic leukemia (CLL); however, the efficacy of therapies for patients whose disease is refractory to/relapses after (R/R) BCRis is unknown. Venetoclax is a selective, orally bioavailable BCL-2 inhibitor with activity in patients with CLL, including those who are heavily pretreated or have 17p deletion. This phase 2 study prospectively evaluated venetoclax in patients with R/R CLL after ibrutinib or Idelalisib; here we report on patients who received Idelalisib as the last BCRi before enrollment. Venetoclax was initiated at 20 mg daily, followed by intrapatient ramp-up to 400 mg daily. Primary objectives included efficacy (objective response rate [ORR]) and safety of venetoclax. The study enrolled 36 patients who previously received Idelalisib (ORR, 67% [24/36]); 2 patients achieved complete remission, and 1 had complete remission with incomplete bone marrow recovery. Median progression-free survival (PFS) has not yet been reached; estimated 12-month PFS was 79%. The most common adverse events (AEs; all grades) were neutropenia (56%), diarrhea (42%), upper respiratory tract infection (39%), thrombocytopenia (36%), nausea (31%), fatigue (28%), cough (22%), rash (22%), and anemia (22%). Grade 3 or 4 AEs were primarily hematologic (neutropenia [50%], thrombocytopenia [25%], and anemia [17%]). No patients experienced tumor lysis syndrome. Venetoclax demonstrated promising clinical activity and favorable tolerability in patients with CLL whose disease progressed during or after Idelalisib therapy. This trial was registered at www.clinicaltrials.gov as #NCT02141282.
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safety of Idelalisib in b cell malignancies integrated analysis of eight clinical trials
Journal of Clinical Oncology, 2015Co-Authors: Steven Coutre, Jennifer R Brown, Susan Obrien, Michael J Keating, Jacqueline C. Barrientos, Sven De Vos, Richard R. Furman, John M. Pagel, Jeff P Sharman, Andrew D. ZelenetzAbstract:e18030 Background: Idelalisib (Zydelig), a first-in-class, selective, oral inhibitor of PI3Kδ, is approved in the US and EU for the treatment of chronic lymphocytic leukemia (CLL) in combination wi...
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Management of adverse events associated with Idelalisib treatment: expert panel opinion
Leukemia & Lymphoma, 2015Co-Authors: Jacqueline C. Barrientos, Michael J Keating, Sven De Vos, Richard R. Furman, Susan O'brien, John M. Pagel, Martin H. PoleskiAbstract:Idelalisib is a first-in-class selective, oral, phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor approved for the treatment of several types of blood cancer. Idelalisib has demonstrated significant efficacy and a tolerable safety profile in clinical trials. However, the US prescribing information contains a black box warning for fatal and/or severe diarrhea or colitis, hepatotoxicity, pneumonitis and intestinal perforation. An expert panel was convened to review the pathology of these treatment-emergent adverse events (TEAEs) to propose key management tools for patients receiving Idelalisib therapy. This article provides an overview of Idelalisib TEAEs reported in clinical trials, and a summary of the panel's recommendations for identification and management of Idelalisib treatment-emergent diarrhea or colitis as well as a discussion of transaminitis and pneumonitis. For Idelalisib-related diarrhea or colitis (including unresolved grade 2 and grade ≥ 3), after exclusion of infectious causes, the panel recommends individualized treatment with budesonide or oral or intravenous steroid therapy.
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Idelalisib-associated Colitis: Histologic Findings in 14 Patients
The American Journal of Surgical Pathology, 2015Co-Authors: Anna Sophie Weidner, Richard R. Furman, Nicole C. Panarelli, Julia T. Geyer, Erica B. Bhavsar, John P. Leonard, Jose Jessurun, Rhonda K. YantissAbstract:Idelalisib is an inhibitor of the PI3Kδ isoform approved for treatment of patients with relapsed chronic lymphocytic leukemia and indolent non-Hodgkin lymphoma. Many patients develop gastrointestinal symptoms during Idelalisib therapy; however, the pathologic effects of this drug have not been characterized. We identified 50 patients who received at least 3 months of Idelalisib therapy. Clinical findings and symptoms were noted for each patient, and endoscopic findings were recorded for those who underwent colonoscopic examination. Hematoxylin and eosin-stained sections from colonic biopsy samples were evaluated for histologic patterns of injury. Twenty-three (46%) patients experienced diarrhea during treatment with Idelalisib, including 8 with severe symptoms (≥7 stools/d above baseline and/or requiring hospitalization). Fourteen patients underwent colonoscopic examination with mucosal biopsy. Twelve (86%) of these had colitis characterized by intraepithelial lymphocytosis, crypt cell apoptosis, and neutrophilic infiltration of crypt epithelium. Eleven patients had symptoms severe enough to warrant drug withdrawal, including 9 who were also treated with corticosteroids. Idelalisib commonly causes diarrheal symptoms in patients undergoing therapy for B-cell neoplasia, which may be severe in nearly 20% of patients. Characteristic histologic features include the combination of intraepithelial lymphocytosis and crypt cell apoptosis, often accompanied by neutrophils. Discontinuation of the drug results in symptomatic improvement and resolution of histologic changes.
Jeff P Sharman - One of the best experts on this subject based on the ideXlab platform.
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Idelalisib immune related toxicity is associated with improved treatment response
Leukemia & Lymphoma, 2021Co-Authors: Nina D Wagnerjohnston, Tadeusz Robak, Jennifer R Brown, Richard R. Furman, Nishanthan Rajakumaraswamy, Jeff P Sharman, Rebecca J Chan, Guan Xing, Gilles Salles, Ajay K. GopalAbstract:Idelalisib is associated with increased occurrence of immune-related adverse events (irAEs). Clinical observations suggest a correlation between immune checkpoint inhibitor-induced irAEs and survival outcomes in patients with solid tumors; however, this relationship in hematologic malignancies is not well understood. In a post hoc analysis of 3 registrational trials, we explored the relationship between Grade ≥3 diarrhea/colitis and alanine/aspartate transaminase (ALT/AST) elevation incidences and efficacy endpoints in patients with indolent non-Hodgkin lymphoma (iNHL), follicular lymphoma (FL), and chronic lymphocytic leukemia treated with Idelalisib. Grade ≥3 diarrhea/colitis was associated with higher overall response rate (ORR) and longer progression-free survival (PFS) for all subgroups. Grade ≥3 ALT/AST elevations were associated with improved duration of response and overall survival for all subgroups and improved ORR and PFS for patients with FL or iNHL. Our analysis in hematologic malignancies showed a trend correlating Idelalisib-induced Grade ≥3 irAEs with improved efficacy.
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Idelalisib in combination with rituximab or bendamustine or both in patients with relapsed refractory chronic lymphocytic leukemia
HemaSphere, 2018Co-Authors: Steven Coutre, Jacqueline C. Barrientos, Sven De Vos, Ian W. Flinn, Jeff P Sharman, Marshall T Schreeder, Thomas E Boyd, Nathan Fowler, Nina Wagnerjohnson, Lyndah DreilingAbstract:AbstractPhosphatidylinositol 3-kinase-delta (PI3Kδ) signaling is critical for proliferation, survival, homing, and tissue retention of malignant B cells. Idelalisib, a selective oral inhibitor of PI3Kδ, has shown considerable single-agent activity in patients with heavily pretreated chronic lymphocy
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combinations of Idelalisib with rituximab and or bendamustine in patients with recurrent indolent non hodgkin lymphoma
Blood Advances, 2016Co-Authors: Sven De Vos, Steven Coutre, Jacqueline C. Barrientos, Ian W. Flinn, Jeff P Sharman, Nina D Wagnerjohnston, Marshall T Schreeder, Nathan Fowler, Ralph V Boccia, Kanti R. RaiAbstract:Idelalisib, a first-in-class oral inhibitor of phosphatidylinositol-3-kinase δ, has shown considerable antitumor activity as a monotherapy in recurrent indolent non-Hodgkin lymphoma (iNHL). To evaluate the safety and activity of Idelalisib in combination with immunotherapy, chemotherapy, or both, 79 patients with relapsed/refractory iNHL were enrolled based on investigator preference in 3 treatment groups. Patients received continuous Idelalisib in combination with (1) rituximab (IR; 375 mg/m2 weekly × 8 doses), (2) bendamustine (IB; 90 mg/m2 per day × 2, for 6 cycles), or (3) both bendamustine and rituximab at aforementioned doses (IBR; monthly × 6 cycles). Patients had a median age of 61 years, a median of 3 prior therapies, and 46% had refractory disease. The overall response rate was 75% (22% complete response) for IR, 88% (36%) for IB, and 79% (43%) for IBR. The median progression-free survival was 37.1 months overall: 29.7 months for IR, 32.8 for IB, and 37.1 months for IBR. The median duration of response was 28.6 months in the IR group and has not been reached in the IB and IBR groups. The most common grade ≥3 adverse events and laboratory abnormalities were neutropenia (41%), pneumonia (19%), transaminase elevations (16%), diarrhea/colitis (15%), and rash (9%). The safety and efficacy reflected in these early data, however, stand in contrast with later observations of significant toxicity in subsequent phase 3 trials in frontline chronic lymphocytic leukemia and less heavily pretreated iNHL patients. Our findings highlight the limitations of phase 1 trial data in the assessment of new regimens. This trial was registered at www.clinicaltrials.gov as #NCT01088048 (an extension study was registered at www.clinicaltrials.gov as #NCT01090414).
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outcomes of patients with relapsed and refractory chronic lymphocytic leukemia cll who discontinue Idelalisib treatment
Journal of Clinical Oncology, 2016Co-Authors: Jennifer R Brown, Jeffrey A. Jones, Terry Newcomb, Jeff P Sharman, Paolo Ghia, Yeonhee Kim, Andrew R. Pettitt, Loic Ysebaert, Stephan Stilgenbauer, Naishun YaoAbstract:7531Background: Idelalisib (IDELA) is effective in the treatment of patients (pts) with relapsed/refractory (R/R) CLL. Nonetheless, pts may discontinue (D/C) IDELA due to progressive disease (PD) o...
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safety of Idelalisib in b cell malignancies integrated analysis of eight clinical trials
Journal of Clinical Oncology, 2015Co-Authors: Steven Coutre, Jennifer R Brown, Susan Obrien, Michael J Keating, Jacqueline C. Barrientos, Sven De Vos, Richard R. Furman, John M. Pagel, Jeff P Sharman, Andrew D. ZelenetzAbstract:e18030 Background: Idelalisib (Zydelig), a first-in-class, selective, oral inhibitor of PI3Kδ, is approved in the US and EU for the treatment of chronic lymphocytic leukemia (CLL) in combination wi...
