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Background: Studies in patients with rheumatoid arthritis and advanced follicular lymphoma have shown that CT-P10, a rituximab biosimilar, has equivalent or non-inferior efficacy and pharmacokinetics to rituximab. We aimed to assess the therapeutic equivalence of single-agent CT-P10 and rituximab in patients with newly diagnosed low-tumour burden follicular lymphoma., Methods: In this ongoing, randomised, double-blind, parallel-group, active-controlled, phase 3 trial, adult patients (≥18 years) with stage II-IV low-tumour-burden follicular lymphoma were randomly assigned (1:1) using an interactive web or voice response system stratified by region, stage, and age to CT-P10 or US-sourced rituximab. Patients received CT-P10 or rituximab (375 mg/m 2 intravenous) on day 1 of four 7-day cycles (induction period). Patients who had disease control after the induction period continued to a maintenance period of CT-P10 or rituximab administered every 8 weeks for six cycles and, if completed, a second year of maintenance therapy of additional CT-P10 (every 8 weeks for six cycles) was offered. The study was partially unmasked after database lock (Feb 23, 2018) for all data up to 7 months (before cycle 3 of the maintenance period). The primary endpoint was the proportion of patients who achieved an overall response by 7 months in the intention-to-treat population. Efficacy equivalence was shown if the two-sided 90% CIs for the treatment difference in the proportion of responders between CT-P10 and rituximab was within the equivalence margin of 17%. This trial is registered with ClinicalTrials.gov, number NCT02260804., Findings: Between Nov 9, 2015, and Jan 4, 2018, 402 patients were assessed for eligibility, of whom 258 were randomly assigned: 130 to CT-P10 and 128 to rituximab. 108 (83%) of 130 patients assigned to CT-P10 and 104 (81%) of 128 assigned to rituximab achieved an overall response by month 7 (treatment difference estimate 1·8%; 90% CI -6·43 to 10·20). Therapeutic equivalence was shown (90% CIs were within the prespecified margin of 17%). The most common grade 3 or 4 treatment-emergent adverse events were decreased neutrophil count (two grade 3 in the CT-P10 group) and neutropenia (one in each group); all other grade 3 or 4 treatment-emergent adverse events occurred in one patient each. Six (5%) of 130 patients who received CT-P10 and three (2%) of 128 who received rituximab experienced at least one treatment-emergent serious adverse event., Interpretation: CT-P10 was equivalent to rituximab in terms of efficacy and was well tolerated. CT-P10 monotherapy is suggested as a new therapeutic option for patients with low-tumour-burden follicular lymphoma., Funding: Celltrion, Inc., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Mantle cell lymphoma (MCL) is an aggressive and incurable lymphoma. Standard of care for younger patients with MCL is induction chemotherapy followed by autologous stem cell transplantation (auto-HCT). Rituximab maintenance after auto-HCT has been shown to improve progression-free survival (PFS) and overall survival (OS) in MCL. Bortezomib maintenance therapy has also been shown to be tolerable and feasible in this setting. However, the combination of bortezomib and rituximab as maintenance therapy post-auto-HCT has not been studied., Methods: We conducted a multicenter, phase II trial of bortezomib given in combination with rituximab as maintenance in MCL patients after consolidative auto-HCT. Enrolled patients (n = 23) received bortezomib 1.3 mg/m 2 subcutaneously weekly for 4 weeks every 3 months (up to 24 months) and rituximab 375 mg/m 2 intravenously weekly for 4 weeks every 6 months (up to 24 months) for a total duration of 2 years. The primary study endpoint was disease-free survival (DFS)., Results: With a median follow-up of 35.9 months, the 2-year DFS probability was 90.2% (95% CI 66-97), and 2-year OS was 94.7% (95% CI 68-99). The most frequent grade 3/4 toxic events were neutropenia (in 74% of patients) and lymphopenia (in 35%). The incidence of peripheral neuropathy was 48% for grade 1, 9% for grade 2, and 0% for grade 3/4. We also examined the role of quantitative cyclin D1 (CCND1) mRNA in monitoring minimal residual disease., Conclusion: Combined bortezomib and rituximab as maintenance therapy in MCL patients following auto-HCT is an active and well-tolerated regimen., Trial Registration: ClinicalTrials.gov NCT01267812 , registered Dec 29, 2010.

Background: Studies in patients with rheumatoid arthritis have shown that the rituximab biosimilar CT-P10 (Celltrion, Incheon, South Korea) has equivalent efficacy and pharmacokinetics to rituximab. In this phase 3 study, we aimed to assess the non-inferior efficacy and pharmacokinetic equivalence of CT-P10 compared with rituximab, when used in combination with cyclophosphamide, vincristine, and prednisone (CVP) in patients with newly diagnosed advanced-stage follicular lymphoma., Methods: In this ongoing, randomised, double-blind, parallel-group, active-controlled study, patients aged 18 years or older with Ann Arbor stage III-IV follicular lymphoma were assigned 1:1 to CVP plus intravenous infusions of 375 mg/m 2 CT-P10 or rituximab on day 1 of eight 21-day cycles. Randomisation was done by the investigators using an interactive web or voice response system and a computer-generated randomisation schedule, prepared by a clinical research organisation. Randomisation was balanced using permuted blocks and was stratified by country, gender, and Follicular Lymphoma International Prognostic Index score (0-2 vs 3-5). Study teams from the sponsor and clinical research organisation, investigators, and patients were masked to treatment assignment. The study was divided into two parts: part 1 assessing equivalence of pharmacokinetics (in the pharmacokinetics subset), and part 2 assessing efficacy in all randomised patients (patients from the pharmacokinetics subset plus additional patients enrolled in part 2). Equivalence of pharmacokinetics was shown if the 90% CIs for the geometric mean ratio of CT-P10 to rituximab in AUCτ and C maxSS were within the bounds of the equivalence margin of 80% and 125%. Non-inferiority of response was shown if the one-sided 97·5% CI lay on the positive side of the -7% margin, using a one-sided test done at the 2·5% significance level. The primary efficacy endpoint was the proportion of patients who had an overall response over eight cycles and was assessed in the efficacy population (all randomised patients). The primary pharmacokinetic endpoints were area under the serum concentration-time curve at steady state (AUCτ) and maximum serum concentration at steady state (C maxSS ) at cycle 4, assessed in the pharmokinetic population. This trial is registered with ClinicalTrials.gov, number NCT02162771., Findings: Between July 28, 2014, and Dec 29, 2015, 140 patients were enrolled. Here we report data for the eight-cycle induction period, up to week 24. The proportion of patients with an overall response in the efficacy population was 64 (97·0%) of 66 patients in the CT-P10 treatment group and 63 (92·6%) of 68 patients in the rituximab treatment group (4·3%; one-sided 97·5% CI -4·25), which lay on the positive side of the predefined non-inferiority margin. The ratio of geometric least squares means (CT-P10/rituximab) was 102·25% (90% CI 94·05-111·17) for AUCτ and 100·67% (93·84-108·00) for C maxSS , with all CIs within the bioequivalence margin of 80-125%. Treatment-emergent adverse events were reported for 58 (83%) of 70 patients in the CT-P10 treatment group and 56 (80%) of 70 in the rituximab treatment group. The most common grade 3 or 4 treatment-emergent adverse event in each treatment group was neutropenia (grade 3, 15 [21%] of 70 patients in the CT-P10 group and seven [10%] of 70 patients in the rituximab group). The proportion of patients who experienced at least one treatment-emergent serious adverse event was 16 (23%) of 70 patients in the CT-P10 group and nine (13%) of 70 patients in the rituximab group., Interpretation: In this study, we show that CT-P10 exhibits non-inferior efficacy and pharmacokinetic equivalence to rituximab. The safety profile of CT-P10 was comparable to that of rituximab. CT-P10 might represent a new therapeutic option for advanced-stage follicular lymphoma., Funding: Celltrion, Inc., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Summary: In a prospective phase II trial, pentostatin combined with cyclophosphamide and rituximab (PCR) induced strong responses and was well‐tolerated in previously untreated patients with advanced‐stage, indolent non‐Hodgkin lymphoma (iNHL). After a median patient follow‐up of more than 108 months, we performed an intent‐to‐treat analysis of our 83 participants. Progression‐free survival (PFS) rates at 108 months for follicular lymphoma (FL), marginal zone lymphoma (MZL) and small lymphocytic lymphoma (SLL) were 71%, 67% and 15%, respectively, and were affected by clinicopathological characteristics. Ten‐year PFS rates for those with beta‐2‐microglobulin levels <2·2 and ≥2·2 mg/l prior to treatment were 71% and 21%, respectively. Patients without bone marrow involvement had 10‐year PFS rates of 72% vs. 29% for those with involvement. At time of analysis, the median overall survival (OS) had not been reached. The OS rate was 64% at 10 years and differed significantly based on histology: 94% for FL, 66% for MZL and 39% for SLL. Long‐term toxicities included 18 (21·7%) patients with second malignancies and 2 (2·4%) who developed myelodysplastic syndrome after receiving additional lines of chemotherapy. Our 10‐year follow‐up analysis confirms that PCR is an effective, robust and tolerable treatment regimen for patients with iNHL. [ABSTRACT FROM AUTHOR]

Background: Although the outcomes of patients with mantle cell lymphoma (MCL) have improved, there is still no cure. Bortezomib has a 33% response rate in relapsed/refractory MCL and has shown additive and/or synergistic effects in preclinical trials with known effective agents.Methods: This is a report of a prospective phase 2 trial of bortezomib added to rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (BzR-hyperCVAD)/rituximab, high-dose methotrexate, and high-dose cytarabine (BzR-MA) for 95 patients with newly diagnosed MCL.Results: The overall and complete response rates were 100% and 82%, respectively. Hematologic toxicity was high but expected and did not lead to an increased incidence of neutropenic fever or dose reductions in comparison with a similar reported regimen without bortezomib. After a median follow-up of 44 months, the median overall survival had not been reached, and the time to treatment failure (TTF) was 55 months, which is not different from that of historical controls.Conclusions: BzR-hyperCVAD/BzR-MA at the dose and schedule studied produced high rates of response and a TTF similar to that of historical reports without bortezomib. Cancer 2018;124:2561-9. © 2018 American Cancer Society. [ABSTRACT FROM AUTHOR]

Intensive chemotherapy regimens containing cytarabine have substantially improved remission durability and overall survival in younger adults with mantle cell lymphoma (MCL). However, there have been no long-term follow-up results for patients treated with these regimens. We present long-term survival outcomes from a pivotal phase II trial of rituximab, hyper-fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with methotrexate and cytarabine (R-HCVAD/MA). At 15 years of follow-up (median: 13·4 years), the median failure-free survival (FFS) and overall survival (OS) for all patients was 4·8 years and 10·7 years, respectively. The FFS seems to have plateaued after 10 years, with an estimated 15-year FFS of 30% in younger patients (≤65 years). Patients who achieved complete response (CR) after 2 cycles had a favourable median FFS of 8·8 years. Six patients developed myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML) whilst in first CR. The 10-year cumulative incidence of MDS/AML of patients in first remission was 6·2% (95% confidence interval: 2·5-12·2%). In patients with newly diagnosed MCL, R-HCVAD/MA showed sustained efficacy, with a median OS exceeding 10 years in all patients and freedom from disease recurrence of nearly 15 years in almost one-third of the younger patients (≤65 years). [ABSTRACT FROM AUTHOR]

We conducted a prospective phase II trial of pentostatin, cyclophosphamide and rituximab as initial therapy for patients with previously untreated advanced stage low-grade or indolent B-cell lymphomas ( iNHLs). Of 83 evaluable patients, 91·6% attained an overall response and 86·8% a complete or unconfirmed complete response. The 3-year progression-free survival ( PFS) and overall survival rates were 73% and 93%, respectively. The 3-year PFS rate was significantly different for different diagnoses ( P = 0·01): 83% [95% confidence interval ( CI): 0·72, 0·96] for follicular lymphomas, 73% (95% CI: 0·54, 1·0) for marginal zone lymphomas and 61% (95% CI: 0·46, 0·81) for small lymphocytic lymphomas. The most common adverse events were haematological. Of 509 cycles of chemotherapy administered, grade 3 or 4 neutropenia was reported in 68 cycles (13% of cycles administered) and most frequently occurred during cycles 4-6. This is the first report demonstrating the effectiveness of pentostatin, cyclophosphamide and rituximab in patients with previously untreated iNHLs, including those over 60 years of age. [ABSTRACT FROM AUTHOR]

We conducted a prospective randomized phase II study to evaluate two chemotherapy regimens: (i) rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone ( R- HCVAD) alternating with rituximab, high-dose methotrexate, and cytarabine ( R- MA) and (ii) rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone ( R- CHOP) in diffuse large B-cell lymphoma ( DLBCL). This study randomized patients aged ≤60 years with DLBCL and an age-adjusted international prognostic index ≥2 to R- HCVAD/ R- MA or R- CHOP based on a Bayesian adaptive algorithm. Interim analysis of the first 26 eligible patients showed that the complete response rate ( CRR) was higher with R- HCVAD/ R- MA than R- CHOP ( P = 0·03); thus, R- CHOP arm was closed. In the final analysis, 49 and 10 eligible patients were treated in R- HCVAD/ R- MA and R- CHOP arms respectively; CRR were 82% and 60% respectively ( P = 0·13); 3-year progression-free survival ( PFS) rates were 75·7% and 77·8% respectively ( P = 0·53). In the R- HCVAD/ R- MA arm, 3-year PFS rates in patients aged 46-60 years and ≤45 years were 70·3% and 87·1% respectively ( P = 0·13), and the treatment-associated early mortality rate in patients >45 years was 12%. In conclusion, R- HCVAD/ R- MA is associated with excellent outcome in patients ≤45 years old. However, in patients >45 years old, R- HCVAD/ R- MA is associated with unacceptable mortality rates. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma (MCL) outcomes have improved over the last two decades; however, late relapses occur. Bortezomib has shown single agent activity of 33% in relapsed MCL and has an additive/synergistic effect in vitro when combined with drugs currently used to treat MCL. We hypothesized that a combination of bortezomib with current intense non-transplant chemoimmunotherapy might prevent late relapses. The toxicity of bortezomib when combined with methotrexate and cytarabine is unknown. Patients aged 18–79 years with untreated aggressive MCL were treated with R-HyperCVAD (rituximab, cyclophosphamide, vincristine, doxorubicin, dexamethasone) alternating with rituximab-methotrexate/cytarabine (R-M/A). Bortezomib was added to the R-Hyper-CVAD combination as a fixed dose of 1·3 mg/m2 IV on days 2 and 5 and was added to the R-M/A regimen after rituximab, in increasing doses of 0·7, 1, and 1·3 mg/m2 in cohorts of three patients. Twenty patients were assessed for toxicity of the regimen. The principal toxicity was haematological and did not differ from that observed with a similar regimen without the bortezomib. In particular, there was no pulmonary or neurological dose-limiting toxicity, showing that bortezomib can be safely combined with R-HyperCVAD and R-M/A. [ABSTRACT FROM AUTHOR]

The article presents the clinical trial of several antineoplastic agents including rituximab, methotrexate, and cytarabine which treat patients with refractory mantle cell lymphoma (MCL) in the U.S. It notes that toxicity, neutropenic fever, and thrombocytopenia are the side effects of the anticancer agents. Moreover, it emphasizes the effectiveness of chemotherapeutic agents including cyclophosphamide, vincristine, and doxorubicin on treating MCL.

Summary Background Standard treatments for indolent non-Hodgkin lymphomas are often toxic, and most patients ultimately relapse. Lenalidomide, an immunomodulatory agent, is effective as monotherapy for relapsed indolent non-Hodgkin lymphoma. We assessed the efficacy and safety of lenalidomide plus rituximab in patients with untreated, advanced stage indolent non-Hodgkin lymphoma. Methods In this phase 2 trial, undertaken at one instution, patients with follicular lymphoma and marginal zone lymphoma were given lenalidomide, orally, at 20 mg/day on days 1–21 of each 28-day cycle. For patients with small lymphocytic lymphoma, dosing began at 10 mg/day to avoid tumour flare, with an escalation of 5 mg/month to 20 mg/day. Rituximab was given at 375 mg/m 2 as an intravenous infusion on day 1 of each cycle. Patients responding after six cycles could continue therapy for up to 12 cycles. The primary endpoint was overall response, defined as the proportion of patients who achieved a partial or complete response; patients were assessed for response if they had any post-baseline tumour assessment. This trial is registered with ClinicalTrials.gov , number NCT00695786 . Findings 110 patients with follicular lymphoma (n=50), marginal zone lymphoma (n=30), and small lymphocytic lymphoma (n=30) were enrolled from June 30, 2008, until Aug 12, 2011. 93 of 103 evaluable patients had an overall response (90%, 95% CI 83–95). Complete responses occurred in 65 (63%, 95% CI 53–72) and partial responses in 28 patients (27%, 19–37). Of 46 evaluable patients with follicular lymphoma, 40 (87%) patients had a complete response and five (11%) had a partial response. Of 27 evaluable patients with marginal zone lymphoma, 18 (67%) had a complete response and six (22%) had a partial response. Of 30 evaluable patients with small lymphocytic lymphoma, seven (23%) had a complete response and 17 (57%) had a partial response. The most common grade 3 or 4 adverse events were neutropenia (38 [35%] of 110 patients), muscle pain (ten [9%]), rash (eight [7%]), cough, dyspnoea, or other pulmonary symptoms (five [5%]), fatigue (five [5%]), thrombosis (five [5%]), and thrombocytopenia (four [4%]). Interpretation Lenalidomide plus rituximab is well tolerated and highly active as initial treatment for indolent non-Hodgkin lymphoma. An international phase 3 study ( NCT01476787 ) to compare this regimen with chemotherapy in patients with untreated follicular lymphoma is in progress. Funding Celgene Corporation and Richard Spencer Lewis Memorial Foundation and Cancer Center Support Grant. [ABSTRACT FROM AUTHOR]

Summary: Background: Endogenous or iatrogenic antitumour immune responses can improve the course of follicular lymphoma, but might be diminished by immune checkpoints in the tumour microenvironment. These checkpoints might include effects of programmed cell death 1 (PD1), a co-inhibitory receptor that impairs T-cell function and is highly expressed on intratumoral T cells. We did this phase 2 trial to investigate the activity of pidilizumab, a humanised anti-PD1 monoclonal antibody, with rituximab in patients with relapsed follicular lymphoma. Methods: We did this open-label, non-randomised trial at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). Adult (≥18 years) patients with rituximab-sensitive follicular lymphoma relapsing after one to four previous therapies were eligible. Pidilizumab was administered at 3 mg/kg intravenously every 4 weeks for four infusions, plus eight optional infusions every 4 weeks for patients with stable disease or better. Starting 17 days after the first infusion of pidilizumab, rituximab was given at 375 mg/m2 intravenously weekly for 4 weeks. The primary endpoint was the proportion of patients who achieved an objective response (complete response plus partial response according to Revised Response Criteria for Malignant Lymphoma). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00904722. Findings: We enrolled 32 patients between Jan 13, 2010, and Jan 20, 2012. Median follow-up was 15·4 months (IQR 10·1–21·0). The combination of pidilizumab and rituximab was well tolerated, with no autoimmune or treatment-related adverse events of grade 3 or 4. The most common adverse events of grade 1 were anaemia (14 patients) and fatigue (13 patients), and the most common adverse event of grade 2 was respiratory infection (five patients). Of the 29 patients evaluable for activity, 19 (66%) achieved an objective response: complete responses were noted in 15 (52%) patients and partial responses in four (14%). Interpretation: The combination of pidilizumab plus rituximab is well tolerated and active in patients with relapsed follicular lymphoma. Our results suggest that immune checkpoint blockade is worthy of further study in follicular lymphoma. Funding: National Institutes of Health, Leukemia and Lymphoma Society, Cure Tech, and University of Texas MD Anderson Cancer Center. [ABSTRACT FROM AUTHOR]

In the present study, we evaluated the efficacy and safety of rituximab In combi-nation with standard doxorubicin, bleomy-cin, vinblastine, and dacarbazine (RABVD) in patients with classical Hodgkin lym-phoma (cHL). In this phase 2 study, patients with chemotherapy-naive, advanced-stage cHL were treated with rituximab 375 mg/m2 weekly for 6 weeks and standard ABVD for 6 cycles. The primary outcome was event-free survival (EFS) at 5 years. Eighty-five patients were enrolled, of whom 78 were eligible. With a median follow-up duration of 68 months (range, 26-110), and based on an intent-to-treat analysis, the 5-year EFS and overall survival rates were 83% and 96%, respec-tively. The 5-year EFS for patients with stage lll/IV cHLwas 82%. Furthermore, the 5-year EFS for patients with an Interna-tional Prognostic Score of 0-2 was 88% and for those with a score of > 2, it was 73%. The most frequent treatment-related grade 3 or 4 adverse events were neutro-penia (23%), fatigue (9%), and nausea (8%). Our results demonstrate that the addition of rituximab to ABVD is safe and has a promising clinical activity in pa-tients with advanced-stage cHL. These data are currently being confirmed in a multi-center randomized trial. This trial has been completed and is registered with www.clini-caltrials.gov as NCT00504504. {Blood. 2012; 119(18):4123-4128) [ABSTRACT FROM AUTHOR]