Lenalidomide, idelalisib, and rituximab are unacceptably toxic in patients with relapsed/refractory indolent lymphoma.
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ABSTRACT:
SUBMITTER: Cheah CY
PROVIDER: S-EPMC5161005 | biostudies-literature | 2015 May
REPOSITORIES: biostudies-literature
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Lenalidomide, idelalisib, and rituximab are unacceptably toxic in patients with relapsed/refractory indolent lymphoma.
Cheah Chan Yoon CY Nastoupil Loretta J LJ Neelapu Sattva S SS Forbes Sheryl G SG Oki Yasuhiro Y Fowler Nathan H NH
Blood 20150501 21
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Project description:BackgroundThe aim of the study was to evaluate the cost-effectiveness of lenalidomide plus rituximab vs rituximab alone in patients with relapsed or refractory indolent lymphoma.MethodsA Markov decision model was established to carry out the cost-effectiveness analysis. Three discrete health states, progression-free survival (PFS), progressive disease (PD), and death, were included. Cycle length was set at 1 month, and utility scores were derived from previously published literature. The incremental cost-effectiveness ratio (ICER) was defined as the primary endpoint, and the willingness-to-pay (WTP) threshold was set at $29,306.43 per quality-adjusted life year (QALY). Both cost and effectiveness were determined using a 3% annual discount rate. Furthermore, one-way and probabilistic sensitivity analyses were performed to check the robustness of the model.ResultsLenalidomide plus rituximab gained 6.08 QALYs at a cost of $120,979.62 while rituximab alone gained 4.84 QALYs at a cost of $48,052.11. The ICER of lenalidomide plus rituximab vs rituximab alone was $58,812.51/QALY. The parameters most significantly influenced the model were the utility values for the PFS state, the duration of the PFS state in the lenalidomide plus rituximab group, and the cost of lenalidomide. The probability of lenalidomide plus rituximab or rituximab alone being the most cost-effective option was 0% and 100%, respectively, at a WTP threshold of $29,306.43/QALY.ConclusionsLenalidomide plus rituximab is not a cost-effective strategy compared with rituximab monotherapy for relapsed or refractory indolent lymphoma from a Chinese societal perspective.
| S-EPMC7402838 | biostudies-literature
Project description:PurposePatients with indolent non-Hodgkin lymphoma typically respond well to first-line immunochemotherapy. At relapse, single-agent rituximab is commonly administered. Data suggest the immunomodulatory agent lenalidomide could increase the activity of rituximab.MethodsA phase III, multicenter, randomized trial of lenalidomide plus rituximab versus placebo plus rituximab was conducted in patients with relapsed and/or refractory follicular or marginal zone lymphoma. Patients received lenalidomide or placebo for 12 cycles plus rituximab once per week for 4 weeks in cycle 1 and day 1 of cycles 2 through 5. The primary end point was progression-free survival per independent radiology review.ResultsA total of 358 patients were randomly assigned to lenalidomide plus rituximab (n = 178) or placebo plus rituximab (n = 180). Infections (63% v 49%), neutropenia (58% v 23%), and cutaneous reactions (32% v 12%) were more common with lenalidomide plus rituximab. Grade 3 or 4 neutropenia (50% v 13%) and leukopenia (7% v 2%) were higher with lenalidomide plus rituximab; no other grade 3 or 4 adverse event differed by 5% or more between groups. Progression-free survival was significantly improved for lenalidomide plus rituximab versus placebo plus rituximab, with a hazard ratio of 0.46 (95% CI, 0.34 to 0.62; P < .001) and median duration of 39.4 months (95% CI, 22.9 months to not reached) versus 14.1 months (95% CI, 11.4 to 16.7 months), respectively.ConclusionLenalidomide improved efficacy of rituximab in patients with recurrent indolent lymphoma, with an acceptable safety profile.
| S-EPMC7035866 | biostudies-literature
Project description:BackgroundPhosphatidylinositol-3-kinase delta (PI3Kδ) mediates B-cell receptor signaling and microenvironmental support signals that promote the growth and survival of malignant B lymphocytes. In a phase 1 study, idelalisib, an orally active selective PI3Kδ inhibitor, showed antitumor activity in patients with previously treated indolent non-Hodgkin's lymphomas.MethodsIn this single-group, open-label, phase 2 study, 125 patients with indolent non-Hodgkin's lymphomas who had not had a response to rituximab and an alkylating agent or had had a relapse within 6 months after receipt of those therapies were administered idelalisib, 150 mg twice daily, until the disease progressed or the patient withdrew from the study. The primary end point was the overall rate of response; secondary end points included the duration of response, progression-free survival, and safety.ResultsThe median age of the patients was 64 years (range, 33 to 87); patients had received a median of four prior therapies (range, 2 to 12). Subtypes of indolent non-Hodgkin's lymphoma included follicular lymphoma (72 patients), small lymphocytic lymphoma (28), marginal-zone lymphoma (15), and lymphoplasmacytic lymphoma with or without Waldenström's macroglobulinemia (10). The response rate was 57% (71 of 125 patients), with 6% meeting the criteria for a complete response. The median time to a response was 1.9 months, the median duration of response was 12.5 months, and the median progression-free survival was 11 months. Similar response rates were observed across all subtypes of indolent non-Hodgkin's lymphoma, though the numbers were small for some categories. The most common adverse events of grade 3 or higher were neutropenia (in 27% of the patients), elevations in aminotransferase levels (in 13%), diarrhea (in 13%), and pneumonia (in 7%).ConclusionsIn this single-group study, idelalisib showed antitumor activity with an acceptable safety profile in patients with indolent non-Hodgkin's lymphoma who had received extensive prior treatment. (Funded by Gilead Sciences and others; ClinicalTrials.gov number, NCT01282424.).
| S-EPMC4039496 | biostudies-literature
Project description:PurposeRituximab and lenalidomide are effective for previously untreated and relapsed/refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). However, long-term survival and predictive biomarkers are not well described.Patients and methodsWe conducted two phase II open-label trials involving 60 patients with previously untreated and R/R advanced-stage iNHL. Patients received lenalidomide and rituximab induction followed by continuous lenalidomide until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR). Correlative studies included plasma cytokine monitoring, flow cytometry of peripheral blood mononuclear cells (PBMC; days 0, 15, 30, and 60), and RNA sequencing (RNA-seq) of pretreatment tumor biopsies.ResultsAt a median follow-up of 63 months for previously untreated and 100 months for R/R, ORR was 82% for both. The 11 R/R patients who achieved complete remission remained in continuous remission for 16 to 141 months, thereafter. Median overall survival (OS) was not reached in the previously untreated and was 140 months (95% confidence interval, 53.4-140) in the R/R group. A mixed-effects linear regression model identified significant associations between Granzyme B+ (GranB+) CD8+ T cells and long-term complete response (LTCR; P = 5.3e-4). Furthermore, prior to start of therapy, treatment response could be predicted by B-cell and GranB+ CD8+ T-cell levels (% total lymphocytes).ConclusionsRituximab plus lenalidomide followed by continuous lenalidomide is effective with manageable toxicity in patients with previously untreated and R/R iNHL. This regimen produces durable remissions, even in heavily pretreated patients, with some lasting greater than 10 years. GranB+ CD8+ T cells, B cells, and plasma IFNγ allowed prediction of LTCR but need validation in larger trials.
| S-EPMC9262142 | biostudies-literature
Project description: Not available
| S-EPMC9430939 | biostudies-literature
Project description:Given the significant activity and tolerability of bendamustine, rituximab, and bortezomib in patients with relapsed indolent and mantle cell non-Hodgkin lymphoma, and laboratory studies suggesting synergistic activity, we conducted a multicenter phase 2 study of the bendamustine/bortezomib/rituximab combination. Patients with relapsed or refractory indolent and mantle cell lymphoma with adequate organ function were treated with bendamustine 90 mg/m² days 1 and 4; rituximab 375 mg/m² day 1, and bortezomib 1.3 mg/m² days 1, 4, 8, 11. Six 28-day cycles were planned. Thirty patients (7 with mantle cell lymphoma) were enrolled and treated. Eight patients experienced serious adverse events, including one event of grade 5 sepsis. Common nonhematologic adverse events were generally grade 1 or grade 2 and included nausea (50%), neuropathy (47%), fatigue (47%), constipation (40%), and fever (40%). Of 29 patients evaluable for efficacy, 24 (83%) achieved an objective response (including 15 with complete response). With median follow-up of 24 months, 2-year progression-free survival is 47% (95% confidence interval, 25%-69%). On the basis of these promising results, the US cooperative groups have initiated randomized trials to evaluate this regimen in follicular and mantle cell lymphoma. This trial was registered at www.clinicaltrials.gov as #NCT00547534.
| S-EPMC3062293 | biostudies-literature
Project description:BackgroundA 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.MethodsA051201 (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/m2 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/m2 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).FindingsBetween 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.InterpretationThe 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.FundingNational Cancer Institute of the National Institutes of Health.
| S-EPMC5499150 | biostudies-literature
Project description: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).
| S-EPMC5737161 | biostudies-literature
Project description: Not available
| S-EPMC10431143 | biostudies-literature
Project description:Outcomes for marginal zone lymphoma (MZL) and follicular lymphoma (FL) remain suboptimal, owing to the limited number of approved agents and the incurable nature of the diseases. BGB-3111-AU-003 was a phase 1/2, open-label, multicenter, single-agent study of the selective Bruton's tyrosine kinase inhibitor zanubrutinib in 385 patients with B-cell malignancies. Here, we present safety and efficacy outcomes for the 53 enrolled patients with relapsed/refractory MZL (n = 20) and relapsed/refractory FL (n = 33), all of whom were enrolled during the part 2 dose expansion, and therefore received zanubrutinib at the recommended phase 2 dose. Treatment with zanubrutinib was generally well tolerated, with most adverse events being ≤ grade 2. Atrial fibrillation/flutter was not reported. Two patients required dose reduction, and 4 patients discontinued treatment because of adverse events. Response was assessed by an independent review committee for MZL and the investigators for FL, per Lugano 2014 classification for non-Hodgkin lymphoma. In patients with MZL, the overall response rate (ORR) was 80%, and the complete response (CR) rate was 20%. With median follow-up of 33.8 months, median progression-free survival (PFS) was not reached. In patients with FL, the ORR was 36.4%, and the CR rate was 18.2%. After a median follow-up of 33.9 months, median PFS was 10.4 months. In conclusion, the results of this study suggest a favorable benefit-risk profile and support zanubrutinib as a potentially meaningful addition to available therapies for patients with relapsed/refractory MZL and FL. This trial was registered at www.clinicaltrials.gov as #NCT02343120.
| S-EPMC9198905 | biostudies-literature