Rituximab Arm Research Articles

Obinutuzumab (GA101) in Combination with FC or CHOP in Patients with Relapsed or Refractory Follicular Lymphoma: Final Results of the Phase I GAUDI Study (BO21000)

Abstract 270Obinutuzumab (GA101), the first type II, glycoengineered, humanized anti-CD20 monoclonal antibody in clinical development, has shown single-agent activity in Phase I and II studies in follicular lymphoma (FL), but no studies have so far examined the safety and activity of GA101 in combination with chemotherapy, or compared GA101 dose levels in large cohorts. This study evaluates the feasibility, safety and efficacy of GA101 in combination with standard chemotherapy regimens for FL at two different doses of GA101.Patients with relapsed or refractory FL (n=56) were stratified by chemotherapy regimen based upon prior treatment history (cyclophosphamide/doxorubicin/vincristine/prednisone [6–8 21 day cycles; n=28] or fludarabine/cyclophosphamide [4–6 28 day cycles; n=28]). Patients were then randomized to one of two GA101 dosing regimens: 1,600 mg on Days 1 and 8 of cycle 1 then 800 mg for subsequent cycles (1,600/800 mg) or 400 mg in all cycles (400/400 mg). These regimens represent a range of active doses in indolent lymphoma, based upon Phase I and II trials in which there were no dose-limiting toxicities. Responding patients were offered maintenance treatment for 2 years or until progression. The primary objective was safety, with response rate a secondary objective. Response was assessed at the end of induction using International Working Group response criteria (Cheson, et al. J Clin Oncol 1999), modified to classify unconfirmed complete response as partial response.Baseline characteristics were similar for both groups (G-CHOP and G-FC, respectively): median age 62.5 and 61.0 years; low-risk FLIPI 29% in both groups; median prior treatments (range) 1 (1–3) and 2 (1–6); bone marrow involvement 25% and 26%; Ann Arbor stage III–IV at study entry 64% and 82%. All patients (28/28) in the G-CHOP arm and 22/28 patients in the G-FC arm completed treatment. Reasons for withdrawal (G-FC arm) were neutropenia (n=3), rash (n=1), infection (n=1) and insufficient response (n=1). The most common AEs in both groups were infusion-related reactions (all grades: 64% G-CHOP; 79% G-FC; Grade 3/4: 7% G-CHOP; 7% G-FC), mostly during the first infusion. Grade 3 or 4 neutropenia was reported in 39% of G-CHOP patients and 50% of G-FC patients. Of 190 cycles of G-CHOP delivered, 11 cycles (6%) were delayed in 8 patients for neutropenia or infection (6 cycles delayed by 1 week; 5 cycles delayed by 2 weeks). Dose of any CHOP component was reduced in 29% of patients, in 5 patients for neuropathy and in 1 patient each because of neutropenia, infection and allergic rhinitis. In the G-FC group, 14 of 135 delivered cycles (10%) were delayed in 10 patients for hematologic toxicity or infections (10 cycles delayed by 1 week; 4 cycles delayed by 2 weeks). Nine of these patients also had a dose reduction in both cytostatic components of the regimen with a further patient having a dose reduction only, for an overall dose reduction in 36% of patients. Three deaths were reported following G-FC induction treatment (progressive disease, n=1; underlying Parkinson’s disease, n=1; and chronic obstructive pulmonary disease during maintenance, n=1), with none considered to be treatment-related. There was no evidence for increased toxicity with the 1,600/800 mg dose compared with the 400/400 mg dose of GA101. The overall response rate (ORR) at the end of induction was 96.4% in the G-CHOP group (39.3% complete response [CR]) and 92.9% in the G-FC group (50.0% CR) (Table). Data from the G-CHOP cohort were compared in a matched-pair analysis to the rituximab plus CHOP (R-CHOP) arm from study M39022 (EORTC 20981) in a similar patient population. Response rates to G-CHOP compared favorably with response rates to R-CHOP.Response rates at end of inductionResponse, n (%)G-CHOPG-FCOverall response27 (96.4)26 (92.9)Complete response11 (39.3)14 (50.0)Partial response16 (57.1)12 (42.9)Stable disease1 (3.6)0Progressive disease01 (3.6)Not assessed01 (3.6)In conclusion, GA101 can be combined safely with chemotherapy regimens used in the treatment of FL, and demonstrates a high level of activity compared with historical controls. G-CHOP could be delivered at the protocol-specified 3-weekly interval in most patients. G-FC in a more heavily pretreated population showed worse tolerability. Following these promising results, GA101 will be studied in combination with CHOP and other chemotherapies in a randomized Phase III study against the standard of care, R-CHOP. Disclosures:Cartron:Roche: Consultancy, Honoraria. Morschhauser:Roche: Honoraria; Celgene: Consultancy, Honoraria. Salles:Roche: Consultancy, Honoraria. Wenger:Roche: Employment. Asikanius:Roche: Employment. Wassner-Fritsch:Roche: Employment. Vitolo:Roche: Membership on an entity's Board of Directors or advisory committees.

A phase II randomized study of lenalidomide or lenalidomide and rituximab as maintenance therapy following standard chemotherapy for patients with high/high-intermediate risk diffuse large B-cell lymphoma.

TPS138 Background: Approximately 40% patients with an intermediate/high to high-risk IPI score will relapse in the first year after completion of standard therapy with R-CHOP. Lenalidomide, an immunomodulatory drug, has activity in relapsed diffuse large B-cell lymphoma (DLBCL). Our pre-clinical data demonstrated that lenalidomide enhances the natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity of rituximab in lymphoma cell lines, inhibits angiogenesis, and alters cytokine production. Methods: This is a phase II randomized study of lenalidomide versus lenalidomide and rituximab. The primary endpoint of the study is to assess the one-year relapse-free survival for patients treated with lenalidomide alone (Arm A) or the combination of lenalidomide and rituximab (Arm B). We expect that a 25% difference in relapse rates compared with current standard therapy will have clinical significance. With a sample size of 32 in each arm, we will have 80% power to detect a difference of 25% between the null hypothesis that the one-year relapse rate is 40% and the alternative hypothesis that the one-year relapse rate is 15% using a two-sided significance level of 2.5%. DLBCL patients with int/high or high-risk IPI score or patients with a positive PET scan mid-therapy will be eligible for the study. Patients on arm A will receive lenalidomide at a dose of 25 mg daily for 21 days of 28 days. Patients on arm B will receive lenalidomide at a dose of 20 mg daily for 21 days along with rituximab on day 8 of even-numbered cycles. Treatment on both arms will be continued for one year. Treatment will be discontinued for disease progression. Lenalidomide dose adjustments are incorporated in the protocol. Correlative studies include performing cytokine analysis at various time intervals (sIL-2R, IL-6, IL-15, IL-12, TNF-a, and IFN-g). Flow cytometric analysis will be performed to assess the change in the number of peripheral blood NK cells (CD4, CD8 and CD56). Genotyping analysis of potentially prognostic DNA polymorphisms (in FCGR3A) will be performed.Thus far, 20 patients of the planned 64 patients have been enrolled.

Short-Term Effects of Rituximab in Children with Steroid- and Calcineurin-Dependent Nephrotic Syndrome

Prednisone and calcineurin inhibitors are the mainstay therapy of idiopathic nephrotic syndrome (INS) in children. However, drug dependence and toxicity associated with protracted use are common. Case series suggest that the anti-CD20 monoclonal antibody rituximab (RTX) may maintain disease remission. This open-label randomized controlled trial was powered to show that a strategy based on RTX and lower doses of prednisone and calcineurin inhibitors was noninferior to standard doses of these agents in maintaining 3-month proteinuria as low as baseline or up to 1 g/d greater (noninferiority margin). Participants were stratified by the presence of toxicity to prednisone/calcineurin inhibitors and centrally assigned to add RTX (Mabthera, 375 mg/m(2) intravenously) to lower doses of standard agents or to continue with current therapy alone. The risk of relapse was a secondary outcome. Fifty-four children (mean age 11 ± 4 years) with INS dependent on prednisone and calcineurin inhibitors for >12 months were randomized. Three-month proteinuria was 70% lower in the RTX arm (95% confidence interval 35% to 86%) as compared with standard therapy arm (intention-to-treat); relapse rates were 18.5% (intervention) and 48.1% (standard arm) (P = 0.029). Probabilities of being drug-free at 3 months were 62.9% and 3.7%, respectively (P < 0.001); 50% of RTX cases were in stable remission without drugs after 9 months. Rituximab and lower doses of prednisone and calcineurin inhibitors are noninferior to standard therapy in maintaining short-term remission in children with INS dependent on both drugs and allow their temporary withdrawal.

Evaluation of the safety of rituximab in combination with a tumor necrosis factor inhibitor and methotrexate in patients with active rheumatoid arthritis: Results from a randomized controlled trial

To assess the safety of rituximab in combination with a tumor necrosis factor (TNF) inhibitor and methotrexate (MTX) in patients with rheumatoid arthritis (RA). Adult patients with active RA (≥ 5 swollen and ≥ 5 tender joints) receiving a stable dose of MTX (10-25 mg/week) and stable dose of TNF inhibitor (etanercept or adalimumab) for ≥ 12 weeks were randomized 2:1 to receive one course of rituximab or placebo, given intravenously at a dose of 2 × 500 mg. The primary end point was the proportion of patients developing ≥ 1 serious infection through week 24. Fifty-one patients were treated with either rituximab or placebo in combination with background MTX and a TNF inhibitor. Baseline characteristics were generally balanced between groups, except for corticosteroid usage (36% in the rituximab arm versus 17% in the placebo arm). A serious infection (pneumonia) was observed in 1 patient (3%) in the rituximab group after 14.4 patient-years of exposure (6.95 events per 100 patient-years, 95% confidence interval 0.98-49.35), compared with none in the placebo group at week 24. Infections were reported in 18 patients (55%) and 11 patients (61%) in the rituximab and placebo groups, respectively. Grade 3 infections were reported in 3 patients (9%) receiving rituximab and in none of the patients receiving placebo. No grade 4 infections were observed, nor were there any opportunistic, fungal, or tuberculosis infections. Serious adverse events (SAEs) were reported in 2 rituximab-treated patients (pneumonia and coronary artery occlusion), whereas there were no SAEs reported in placebo-treated patients. At week 24, the percentage of patients achieving an American College of Rheumatology 20% (ACR20) improvement response was 30% in the rituximab group compared with 17% in the placebo group, and ACR50 responses were achieved by 12% and 6% of patients, respectively. The preliminary safety profile of rituximab in combination with a TNF inhibitor and MTX was consistent with the safety profile of rituximab in combination with MTX in other RA trials without a TNF inhibitor, with no new safety signals observed. SAEs were numerically more frequent in the rituximab group, and there was no clear evidence of an efficacy advantage in patients receiving rituximab in combination with a TNF inhibitor and MTX.

An Intergroup Randomised Trial of Rituximab Versus a Watch and Wait Strategy In Patients with Stage II, III, IV, Asymptomatic, Non-Bulky Follicular Lymphoma (Grades 1, 2 and 3a). A Preliminary Analysis

Abstract 6 Patients with asymptomatic, advanced stage, follicular lymphoma have shown no benefit of immediate chemotherapy when compared with a watchful-waiting approach, whereby chemotherapy is deferred until disease progression. Deferring chemotherapy may spare the patient the side effects of the chemotherapy in the short term and historically this has been the preferred approach. With the advent of rituximab and its relatively favourable side effect profile we designed this study to compare a watchful waiting approach with immediate treatment with rituximab. Adult patients with asymptomatic stage 2, 3 or 4 follicular lymphoma (grades 1–2 & 3a) and adequate bone marrow reserve were randomly assigned with a ratio 1:1:1 to watchful waiting (arm A) or rituximab 375mg/m2 weekly for 4 weeks (arm B) or rituximab 375mg/m2 weekly for 4 weeks followed by rituximab maintenance every 2 months for 2 years (starting at month 3 until month 25)(arm C). The primary endpoints were a) time to initiation of new therapy (chemotherapy or radiotherapy) and b) effect on quality of life. The study was designed to detect an improvement in the median time to initiation of therapy in each of the rituximab arms of 18 months (from 30 months to 48 months) with 2.5% significance level and 90% power. A total of 230 events were required and 600 patients were planned. In September 2007, a decision was made to discontinue arm B as evidence of the efficacy of maintenance rituximab became clear. With the two arms comparison, using a significance level of 5%, a total of 360 patients in Arm A and Arm C were planned. Between September 2004 and May 2009 462 patients were randomised (186 Arm A, 84 Arm B, and 192 Arm C). 95% of patients had low tumour burden (GELF criteria) the other 5% had raised LDH but fulfilled the remaining GELF criteria. 98% were entered into the study within 4 months of diagnostic biopsy. Median age 60yr (range27-87). 54% female. ECOG performance status 0=91% & 1=9%. Grade 1–2=89%. Stage 2(21%), stage 3(40%), stage 4 (39%). 42% had bone marrow involvement. FLIPI score: 0=9%, 1=26%, 2=41%, 3=22%, 4=2%. In March 2010 the Data Monitoring committee concluded that the data regarding time to initiation of new therapy was mature and recommended full analysis of data to be performed and presented in the knowledge that rituximab maintenance was still ongoing in 20 patients. To date 45 SAEs have been reported (Arms A=14, B=6, C=25), 14 SAE were considered possibly, probably or definitely related to the study drug (Arm B=4, C=10). 5 allergic reactions (two grade 3), 6 infections, 3 episodes of grade 4 neutropenia. Responses were assessed at month 7, 13 and 25. CT was compulsory at months 7 and 25. Bone marrow was only required if CR on clinical and CT criteria. An interim analysis was performed on 9 Feb 2010. At month 7: Arm A: spontaneous remission was seen in 3%, PR=6%, NC (no change) =74%, PD=17%. Arm B: CR+CRu=45%, PR=33%, NC=19%, PD=3%. Arm C: CR+CRu=49%, PR=36%, NC=11%, PD=3%. At the time of the interim analysis 93 (20%) patients had initiated new treatment. Of these 93 patients 84 (90%) had clinically reported progression. New treatment was chemotherapy in 78 (84%), radiotherapy in 10 (11%), rituximab monotherapy in 2 (2%), surgery in 1(1%),currently not known in 2 (2%). The estimated median time to initiation of new therapy in arm A was 33 months, similar to our previous trial of watchful waiting (Ardeshna et al Lancet 2003). The time to initiation of new therapy was significantly longer in the rituximab arms (fig 1, p value of log-rank test 0.5). These data indicate that initial treatment with rituximab significantly delays the need for new therapy and this finding may change the management of patients with newly diagnosed asymptomatic follicular lymphoma. Disclosures: Ardeshna:Roche: Funding data manager, Honoraria, Membership on an entity9s Board of Directors or advisory committees. Off Label Use: Rituximab is currently not licensed for use as a single agent in previously untreated patients with with asymptomatic advanced stage follicular lymphoma. Pocock:Roche: Honoraria, Membership on an entity9s Board of Directors or advisory committees. Cunningham:Roche: Research Funding. Davies:Roche: Honoraria, Membership on an entity9s Board of Directors or advisory committees; chugai: Honoraria, Research Funding. Walewski:Roche: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau. Linch:Roche: Honoraria, Membership on an entity9s Board of Directors or advisory committees.

Chlorambucil Plus Rituximab Produces Better Event-Free Survival in Comparison with Chlorambucil Alone in the Treatment of MALT Lymphoma: 5-Year Analysis of the 2-Arms Part of the IELSG-19 Randomized Study

AbstractAbstract 432The IELSG-19 study was launched in 2003 by the International Extranodal Lymphoma Study Group to compare Chlorambucil alone versus the combination of Chlorambucil and Rituximab in the treatment of MALT lymphomas. Main contributors were the Italian Lymphoma Intergroup, the French GELA Group, the UK NCRI Group, the Catalan Hematology Group and the Oncology Institute of Southern Switzerland. MALT lymphoma pts with localized disease at any extranodal site who did not respond or were not suitable for local therapy (including H.pylori-negative gastric lymphomas or those who failed antibiotic therapy) were eligible, as well as those with disseminated or multifocal MALT lymphoma. Central histology review was performed. In arm A, Chlorambucil was given 6 mg/m2 daily p.o for 42 consecutive days (d 1–42). After restaging, responding patients and those with stable disease were kept on Chlorambucil 6 mg/m2 daily p.o for 14 consecutive days every 28 days for 4 cycles (d 56–70, 84–98, 112–126, 140–154). In arm B, Chlorambucil was given as in arm A, together with Rituximab, 375 mg/m2 iv on day 1, 8, 15, 22, 56, 84, 112 and 140. Because of the excellent initial recruitment a third arm with Rituximab alone (with a randomisation rate of 1:1:6) was introduced in 2006. The study planned accrual of 450 patients was reached in June 2010. A planned final analysis was performed according to protocol on the 227 pts enrolled in the first two arms before introduction of the third treatment arm: 119 men (52%) and 108 women (48%); 204 (90%) with no previous treatment. The sample size allowed the detection of a 20% improvement in event-free survival (EFS, main endpoint) with 5% significance and 80% power. The treatment was completed as per protocol in 86% of the 227 pts analysed (89% in Arm A and 80% in arm B, respectively), in 60% without any dose adjustment or delay. The primary MALT lymphoma site was the stomach in 94 pts (41%);133 pts (59%) had a non-gastric presentation. In 79 pts (35%) the lymphoma involved more than 1 extranodal site. Lymph node involvement was present in 85 pts (37%); 133 pts (59%) had localized disease (Ann Arbor stage I-II). The ECOG performance status was 0 in 168 pts (74%). According to the international prognostic index (IPI) 133 pts (59%) had a low risk, 48 (21%) a low-intermediate risk, 39 (17%) an intermediate-high risk, and only 7 (3%) a high risk score. B-symptoms were present in 21 pts (9%) and LDH levels were higher than normal in 17 (7%). The main risk factors were equally distributed between the two arms. Outcome analysis was performed on all randomised patients on an intent-to-treat basis, median follow-up time is 60 months. The 5-year EFS was significantly better for the patients treated with Chlorambucil plus Rituximab (68%; 95% CI, 58%-76%) in comparison with those receiving Chlorambucil alone (50%; 95% CI, 40%-59%). Overall survival (OS) at 5 years was identical in the two arms (88%). There was no outcome difference between pts with gastric and non-gastric localization (note that H. pylori-positive gastric MALT lymphoma pts still responding to antibiotics were not eligible). Among the main clinical characteristics, more than one extranodal site, advanced stage, the presence of lymph nodal involvement and an unfavourable IPI were significantly associated with shorter EFS and OS. With respect to toxicity, both treatments were well tolerated and no unexpected side effects were recorded. Severe hematologic toxicity was uncommon in both arms but grade 3–4 neutropenia was significantly more frequent in the Chlorambucil plus Rituximab arm (19 vs. 2 episodes, p<0.001). In conclusion, this is the largest randomised trial ever conducted in MALT lymphoma. While awaiting the analysis of the whole study (to include the third arm with Rituximab alone, added later on), the current results confirm the activity of Rituximab in combination with chemotherapy but also indicate that differences in EFS and response rate may not automatically translate into improved survival overall.Table 1AllArm A ChlorambucilArm B R-Chlorambucilp-valuen227113114sex (M/F)119/10863/5056/58n.s.median age (years)606059n.s.previously untreated204100104n.s.primary gastric site944846n.s.primary non-gastric site1336568n.s.lymph node involvement854243n.s.low to low-intermediate IPI1819091n.s.median follow up (months)606062n.s.5-year EFS59%50%68%0.0024best response-CR71%65%78%0.017-PR19%22%16%5-yr OS88%88%88%n.s. [Display omitted] Disclosure:Zucca:Roche: Research Funding; Mundipharma: Honoraria, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Among indolent lymphomas, Rituximab is not specifically approved for MALT lymphoma but only for follicular lymphoma. Johnson:Roche: Membership on an entity's Board of Directors or advisory committees. Vitolo:Roche: Membership on an entity's Board of Directors or advisory committees. Coiffier:Roche: Research Funding. Morschhauser:Roche: Honoraria. Pettengell:Roche: Honoraria.

Randomised Intergroup Trial of First line Treatment for young Low-Risk Patients (

AbstractAbstract 111 Background:The addition of rituximab to CHOP-21 significantly improved clinical outcome in elderly patients with DLBCL (Coiffier et al., 2002). The MInT trial, randomized young good-prognosis patients to receive a CHOP-like regimen or the same CHOP-like regimen plus rituximab, and was stopped early because of superiority of the rituximab arm, and results were published with a median follow-up of 34 months (Pfreundschuh et al., Lancet Oncology 2006; 379-91). Objective:Because the MInT study was the first study to show a survival benefit with the addition of rituximab to a CHOP-like regimen in young good-prognosis patients, extended follow-up is important to determine whether the survival benefit is maintained over time and whether a definitive effect on cure rates can be shown. Methods:In a phase III intergroup study with participating cooperative groups from 18 countries, previously untreated patients (18-60 years) with low-risk DLBCL (age-adjusted IPI 0 or 1, stages II-IV and stage I with bulky disease) were randomized to receive 6 cycles of a CHOP-like regimen (CHEMO) or the same chemotherapy plus rituximab 375 mg/m2, given on day 1 of each 3-week regimen and on days 1, 22, 43, 64, 85 and 106 of the 2-week regimens, respectively (R-CHEMO). Radiotherapy (30-40 Gy) was planned to sites of initial bulky disease and/or extranodal involvement. The primary endpoint was event-free survival (EFS) with events defined as failure to achieve complete remission, progressive disease, relapse, death or additional therapy. The trial was powered to show a 10% difference in EFS rate after 3 years. Results:Between 05/2000 and 10/2003 a total of 823 patients were recruited of whom 396 were allocated to receive CHOP-21, 361 to CHOEP-21, 34 to MACOP-B, and 32 to PMitCEBO with or without rituximab. Toxicity, incidence of adverse events and severe adverse events in the CHEMO and the R-CHEMO arms were not significantly different. After a median follow-up of 70 (0.03-117) months, patients assigned to chemotherapy and rituximab had increased 6-year event-free survival compared with those assigned to chemotherapy alone (74.0% [95% CI 69.0–78.3] vs 55.7% [50.3-60.8]; log-rank p<0·0001), increased 6-year progression-free survival (79.9% [75.1 - 83.8%] vs 63.8% [58.2-68.8]; log-rank p<0.001) and increased overall survival (89.8% [86.0-92.6] vs 80.0% [75.3-83.9; log rank p=0.001). In a multivariate analysis event-free survival was affected by the addition of rituximab (hazard ratio [HR] 0.49, p< 0.001), age-adjusted IPI (HR 1.73, p<0.001), and bulky disease (HR 1.43, p=0.004). Similar effects were observed for OS, while PFS was affected by treatment arm (HR 0.49, p<0.001) and age-adjusted IPI (HR 1.8, p<0.001). As a consequence, a very favorable subgroup (aaIPI=0, no bulky) can be distinguished from a less favorable subgroup (aaIPI=1 and/or bulky disease) among good-prognosis patients treated with rituximab. There were 10 late (>60 months) events after CHEMO (61.4 to 96.1 months), including 4 in the very favorable subgroup, while all 8 late events (67.5 to 105.7 months) after R-CHEMO occurred in the less favorable subgroup only, and none in the very favorable subgroup. Conclusion:Addition of rituximab to a CHOP-like regimen leads to a significant improvement of the outcome in young patients with good-prognosis diffuse large B-cell lymphoma, with significant survival benefit maintained during a 6-year follow-up. However, except in the very favorable subgroup after R-CHEMO, late relapses after 5 years occur. While reduction of treatment in a randomized study like the FLYER trial of the DSHNHL is justified, further progress, e.g. by dose densification (UNFOLDER trial of the DSHNHL) and/ or dose escalation is still warranted for the less favorable subgroup. Supported by Roche, Deutsche Krebshilfe and KML. Disclosures:Pfreundschuh:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Trneny:Roche: Honoraria, Research Funding. Walewski:Roche: Honoraria, Research Funding. Pettengell:Roche: Honoraria. Jäger:Roche: Honoraria, Research Funding. Lopez-Guillermo:Roche: Consultancy.

The Role of the Rituximab Partner Chemotherapy Regimen In Young Patients with Good-Prognosis Diffuse Large B-Cell Lymphoma (DLBCL): Results of the 6-Year Follow-up of the Mint Study of the Mabthera International Trial (MInT) Group.

AbstractAbstract 2826 Background:The addition of rituximab to CHOP-21 significantly improved clinical outcome in elderly patients with DLBCL (Coiffier et al., 2002). In young patients, the MInT trial, where young good-prognosis patients were randomized to receive a CHOP-like regimen or the same CHOP-like regimen plus rituximab, had to be stopped early because of superiority of the rituximab arm, and results were published with a median follow-up of 34 months (Pfreundschuh et al., Lancet Oncology 2006;379–91). Objective:Because the MInT study was the first study to show a survival benefit of the addition of rituximab to a CHOP-like regimen in young good-prognosis patients, it is important to analyze the effect of different chemotherapy regimens on long-term outcome. Methods:In a phase III intergroup study with participating cooperative groups from 18 countries, previously untreated young (18-60 years) patients with good-prognosis DLBCL (age-adjusted IPI 0 or 1, stages II-IV and stage I with bulky disease) were randomized to receive 6 cycles of a CHOP-like regimen (CHEMO) or the same chemotherapy plus rituximab 375 mg/m2, given on day 1 of each 3-weekly regimen and on days 1, 22, 43, 64, 85 and 106 of the 2-week regimens, respectively (R-CHEMO). Radiotherapy (30-40 Gy) was planned to sites of initial bulky disease and/or extranodal involvement. The primary endpoint was event-free survival (EFS) with events defined as failure to achieve complete remission, progressive disease, relapse, death or additional (unplanned) therapy. Results:Between 05/2000 and 10/2003 a total of 823 patients were recruited of whom 396 were allocated to receive CHOP-21, 361 to CHOEP-21, 34 to MACOP-B, and 32 to PMitCEBO with or without rituximab. Patients'characteristics were not different between the treatment arms with the exception that patients in the MACOP-B and R-MACOP-B arm had a more favorable prognostic profile. Toxicity, incidence of adverse events and severe adverse events in the different CHEMO and the R-CHEMO arms were not significantly different. After a median observation time of 70 (0.03-117) months, the 6-year EFS rates of patients assigned to CHEMO only were 50.4%, 60%, 41.7%, and 78.6% for CHOP-21, CHOEP-21, PMitCEBO, and MACOP-B, respectively. In an adjusted multivariate Cox regression model for EFS restricted to CHEMO patients, only the CHOEP-21 hazard ratio (HR) was significant (HR=0.73; p=0.05) compared to CHOP-21, while the hazard ratios of the different chemotherapies were not significantly different for PFS and OS (6 year PFS-rates: 60.2%, 64.8%, 67.5%, 86.2%; and 6 year OS-rates: 78.8%, 80.2%, 65.5%, and 100.0%, respectively). In patients assigned to R-CHEMO, 6-year EFS rates were 74.9%, 75%, 36.5%, and 86.7% for CHOP-21, CHOEP-21, PMitCEBO and MACOP-B, respectively. Likewise, PMitCEBO patients tended to have lower PFS (6-year rates: 79.1%, 81.9%, 58.9, and 86.7%, respectively) and OS (6-year rates: 91.9%, 89.4%, 80.0 and 94.1%, respectively). The poor outcome after R-PMitCEBO in contrast to R-CHOP was confirmed by multivariable Cox regression restricted to R-CHEMO and adjusting for aaIPI and bulky disease. Hazard ratio of PMitCEBO was significant for EFS (HR 4.35, p<0.001) and PFS (HR 3.62, p=0.002), with a strong trend for OS (HR 3.11, p=0.073). Conclusion:While the addition of rituximab to CHOP-like regimens usually results in reduced differences between chemotherapy regimens (“chemo-equalizer” effect, e.g. disappearance of the superiority of CHOEP over CHOP after the addition of rituximab), combination of rituximab with some regimens might result in an unexpectedly poor outcome. Therefore, rituximab should not be combined with regimens other than CHOP outside randomized trials. Supported by Roche, Deutsche Krebshilfe and KML. Disclosures:Jäger:Roche: Honoraria, Research Funding. Pettengell:Roche: Honoraria. Pfreundschuh:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees.

Efficacy and safety of different doses and retreatment of rituximab: a randomised, placebo-controlled trial in patients who are biological naïve with active rheumatoid arthritis and an inadequate response to methotrexate (Study Evaluating Rituximab's Efficacy in MTX iNadequate rEsponders (SERENE))

ObjectivesThis phase III study evaluated the efficacy and safety of rituximab plus methotrexate (MTX) in patients with active rheumatoid arthritis (RA) who had an inadequate response to MTX and who...

Cost Effectiveness of Rituximab Maintenance Therapy in Follicular Lymphoma

Rituximab maintenance therapy was shown to significantly extend overall survival (OS) and progression-free survival (PFS) in relapsed/refractory follicular lymphoma (FL) in the pivotal EORTC 20981 trial. To assess the long-term costs and cost effectiveness of rituximab maintenance therapy after induction therapy versus current standard practice (observation) from the French National Health Service perspective. A lifetime transition model was developed comparing rituximab maintenance with observation. PFS and OS were obtained from the EORTC 20981 trial with a median follow-up of 28 months and extrapolated from 2-year Kaplan-Meier curves using a Weibull distribution. PFS and OS benefits of rituximab were conservatively assumed to last only 5 years. Utility data were obtained from a multicentre observational study using the EQ-5D questionnaire. Direct medical costs were obtained from French official sources. All costs are reported in euro, year 2006 values. The EORTC 20981 study demonstrated that rituximab maintenance was effective in the management of relapsed/refractory FL. The model results showed that life expectancy and QALYs were increased by 22% and 28%, respectively, in patients treated with rituximab. The incremental cost-effectiveness ratios (ICERs) were euro 7612 per life-year gained and euro 8729 per QALY gained. In a one-way sensitivity analysis, most of the ICERs fell within the range of euro 7000-12,000. The results tend to show that rituximab maintenance therapy may be a cost-effective strategy in the management of relapsed/refractory FL in France, with ICERs below those observed for other therapies in the oncology field. The cost of rituximab was partly offset by the lower cost of relapse due to a longer time in the disease-free health state for patients in the rituximab arm.

Long Term Follow up Analysis Following Front Line Therapy with Dexamethasone or Dexamethasone Plus Rituximab in Adults with Primary Immune Thrombocytopenia.

Abstract 2415Poster Board II-392We previously reported that in adults with primary immune thrombocytopenia (ITP) the addition of four weekly administrations of rituximab 375 mg/m2 to a single course of dexamethasone (40 mg daily for four days) improves the rate of sustained response (SR, i.e. platelet count 3 50 × 109/L at month 6 from the beginning of treatment) if compared with dexamethasone alone (63% vs 36%, P= 0.004, 95% C.I.: [0.079-0.455]) (ML18542 study, Zaja et al. Blood 2008; 112:Abstract 1). Moreover, the rate of SR in 27 patients receiving dexamethasone plus rituximab salvage therapy because of primary refractoriness or relapse after dexamethasone monotherapy was 56%. In order to better address the impact of therapy beyond month 6, a subsequent observational follow-up study up which lasted from month 6 up to month 36 was planned. Participating centers were asked to continue to monitor the patients enrolled in the ML18542 study at least every 4 months up to the end of year 3 from accrual, documenting the occurrence of delayed side effects, the response status and the need for further treatment. We considered as efficacy parameters the duration of response (RD), i.e. the interval between achievement of SR and relapse, the relapse rate (number of patients who lost their SR status) and the need of further specific anti ITP therapy after month 6 (TFS). Eighty out of the original 101 patients enrolled in the ML18542 study, 15 treated with the dexamethasone monotherapy arm, 41 with the dexamethasone plus rituximab arm and 24 who received dexamethasone plus rituximab salvage therapy, were systematically followed-up beyond month 6 for a median overall period of observation of 20 months (range: 4-40 months). Twenty-one patients could not be valuable, most of them because lost at follow up during the study period. As far as the safety profile, we documented one single case of Herpes Zoster reactivation at month 22 in a patient initially allocated to the dexamethasone arm who further received dexamethasone plus rituximab salvage therapy. No other infectious, delayed toxic events or deaths were registered. Fifty-three out 80 patients who achieved a SR according to the study protocol could be evaluated for long term efficacy. This group included 13 patients from the dexamethasone monotherapy arm who were observed after month 6 for a median period of 20 months (range: 12-28 months), 26 of dexamethasone plus rituximab arm observed for a median period of 24 months (range: 8-40 months), and 14 from the dexamethasone plus rituximab salvage therapy group observed for a median period of 20 months (range: 12-34). The rate of relapse in the three groups was 23% (3/13), 23% (6/26), and 14% (2/14) respectively (Fisher test, P= 0.824). The 30 months estimated probability of RD within each of the three treatment groups was 77%, 71%, and 85% (Log-rank test, P= 0.755), respectively. The time of SR loss was comprised between month 4 and 30 in the dexamethasone monotherapy arm, month 4 and 40 in the experimental arm, and month 8 and 34 in the salvage therapy arm. In these three groups, the use of further specific anti ITP therapy after month 6 was registered in 33%, 29% and 36% of patients (Fisher test, P= 1), respectively. Overall, in this period of observation 4 out 80 (5%) valuable patients underwent splenectomy. In conclusion the results of this study indicate: i) similar and very low pattern of long term toxicity between ITP patients treated either with single course of dexamethasone or dexamethasone plus rituximab; ii) no significant differences in the relapse rate, RD and TFS among patients who achieved SR after dexamethasone monotherapy or dexamethasone plus rituximab, either front line or salvage therapy, suggesting that relapse rate may be a possible surrogate of SR, rather than of the initial therapeutic choice. Disclosures:Zaja:Roche: Honoraria, Research Funding, financial support for the costs of travel to the ASH annual meeting. Off Label Use: Rituximab in ITP.

How Much Rituximab Do We Need: A Multicenter, Randomized Trial Comparing 1, 3 or 6 Infusions of Rituximab Combined with 6 Cycles of CHOP Chemotherapy in Untreated Patients with Advanced Follicular Lymphoma (HD2000-Trial).

Abstract 2687Poster Board II-663 Background:The addition of Rituximab to standard chemotherapy has substantially improved the prognosis of NHL. Over the last years, a trend towards intensified protocols with multiple applications of Rituximab has been observed. We are able to report a unique cohort that has also been treated with only 1 or 3 courses of Rituximab within a prospective randomized phase II trial, contrasting current standard procedures. Patients and Methods:Between 2000 and 2005, 126 patients (pts) with stage III/ IV CD20+ follicular lymphoma (FL) were randomized in a prospective multicenter trial to receive 1, 3 or 6 courses Rituximab with 6 courses standard CHOP chemotherapy. The primary endpoint was to compare the three treatment arms with regards to molecular remission rates (mRR) among pts with positive PCR at diagnosis. Secondary endpoints were clinical remission rates, progression-free (PFS) and overall-survival (OS) and toxicity. After screening failure (n = 21) or protocol violation (n = 6) had occurred, 99 pts form the base for this analysis. Among those, only 28 pts were PCR positive at start of treatment and met the criteria for inclusion into the primary endpoint analysis. Results:Due to a limited number of evaluable pts, mRR and duration of molecular remission could not be analyzed. Among 99 pts eligible for the secondary endpoint analysis, 31 received 1 course of Rituximab (arm A), 36 received 3 courses (arm B) and 32 received 6 (arm C). 42% were male. The median age at diagnosis was 56 years (range 23–79). Histological grade was 1 in 49%, 2 in 35% and 3 in 12%. Stage according to Ann Arbor was 3 in 30% and 4 in 70% of pts. B symptoms were present in 36%. According to FLIPI, 21% were classified as low risk (0–1), 39% as intermediate risk (2), and 39% as high risk (3–5). At least one extranodal manifestation was detected in 81 pts, with over 60% of extranodal manifestations being located in the bone marrow. Bulky disease was detected in 57 pts. Following immunochemotherapy, 37% received consolidating involved-field radiotherapy. There was no difference between the three treatment arms with regards to presenting or demographic characteristics (p>.05). Treatment was terminated prematurely in 19 pts due to protocol violation (n = 10), stable disease/ disease progression (n=5), pts′ preference (n = 3) or death (n = 1). After completion of immunochemotherapy, 29 of 99 pts had achieved CR and 58 PR; no or minimal response or progression was observed in 6 pts, and 6 pts were not evaluable. There was no statistically significant difference of clinical remission status between pts in arm A and B compared to those in arm C (p = .66), and between pts in arm B and C compared to arm A (p = .07). There was no trend in clinical remission rates through different courses of Rituximab (p = .09). However, 3 courses were not inferior to 6 courses with regards to clinical remission rate. After a median follow-up of 60 months (range 4–90) 94% of pts in each arm had achieved at least PR. Relapse occurred in 36 pts, with no significant difference in remission duration between the three arms (p = .28). In comparison to 1 course, multiple courses did not significantly prolong the duration of remission (p = .12). 6-year PFS was 45% in arm A, 60% in arm B and 65% in arm C, with no difference between the three arms (p = .35). Neither 3 (p = .29) nor 6 courses (p = .18) did significantly alter PFS compared to 1 course. The difference in PFS between 1 course vs. 3 or 6 courses was not significant (p =.16). 6-year OS was 72% in arm A, 82% in arm B and 80% in arm C, with no significant difference between the three arms (p = .46). Neither 3 (p = .26) nor 6 courses (p = .36) significantly altered OS when compared to 1 course. The difference in OS between 1 course vs. 3 or 6 courses was also not significant (p = .22). Toxicities most frequently observed were grade 3/4 leucopenia. There was no difference with regards to infections (p = .67) and allergic reactions (p = .70). Death occurred in 18 pts. Conclusion:There was no difference in remission rates, remission duration, PFS and OS between pts treated with different courses of Rituximab, with more frequent applications not differing from less frequent applications. In this study, a non-inferiority of fewer applications of Rituximab could not be detected. Therefore, the advantage of multiple courses of Rituximab remains uncertain. To our knowledge, this is the first study that randomized pts to receive fewer doses of Rituximab than currently applied in standard protocols. Disclosures:No relevant conflicts of interest to declare.

A Prospective Randomized Study Comparing Rituximab and Dexamethasone Vs Dexamethasone Alone in ITP: Results of Final Analysis and Long Term Follow up

Introduction. Previous uncontrolled studies have highlighted the activity of rituximab in patients with idiopathic thrombocytopenic purpura (ITP) relapsed or refractory to standard treatments. To better address this effect, a prospective randomized (1:1), multicenter, phase III study comparing treatment with dexamethasone alone (arm A) vs dexamethasone plus rituximab (arm B) was conducted from July 2005 through June 2007 for adult patients with previously untreated ITP and a platelet (PLT) count ≤20 × 109/L.Material and methods. Patients randomized to arm A received a single course of oral dexamethasone 40 mg on days +1, +2, +3, +4, while patients randomized to arm B received dexamethasone (as in arm A) in association with rituximab 375 mg/m2 iv on days +7, +14, +21, +28. Patients in arm A who failed to achieve a sustained response and had a platelet count ≤20 × 109/L (from day +30 up to the end of 6 months) could receive salvage treatment with the experimental arm (dexamethasone plus rituximab). The primary objective of the study was to compare the sustained response (SR), i.e. PLT count 50 × 109/L at month + 6 of treatment. Secondary objectives were: evaluation of the safety, the initial response (PLT count 50 × 109/L) by day 30 after the initiation of treatment, the activity of salvage therapy with dexamethasone plus rituximab in patients non responding to dexamethasone monotherapy, the definition of clinical and laboratory factors predictive of response and to explore the pharmacokinetics parameters of rituximab and their potential relation with response. Results were analyzed by an intention to treat (ITT) and by a per-protocol (PP) analysis.Results. One-hundred-one patients (52 for arm A and 49 for arm B) and 64 patients (38 for arm A and 26 for arm B) represented the ITT and PP population, respectively. Demographic baseline data were in accordance to what expected for a population of ITP patients. No significant differences among the two groups of randomization were present. There was a female prevalence and the mean age was 47 and 49 years in arm A and B, respectively. Table 1 summarizes the ITT and PP efficacy results considering 3 different levels of response (i.e. PLT count 50 × 109/L, 100 × 109/L and 150 × 109/L). A significant advantage for arm B patients was documented.Table 1Initial responseInitial responseSustained responseSustained responseAnalysisIntention-to TreatPer-ProtocolIntention-to TreatPer-ProtocolTreatmentArm AArm BP valueArm AArm BP valueArm AArm BP valueArm AArm BP valueValuable patients4425321352493826PLT3 50×109/L27%68%.00131%69%.00936%63%.00439%85%<.001PLT3 100×109/L23%48%.01528%46%.12233%53%.01937%77%<.001PLT3 150×109/L18%36%.17822%38%.12725%43%.02929%65%.002Twenty-seven patients initially allocated to arm A and who failed to achieve initial response or SR received salvage treatment with the dexamethasone plus rituximab. In this group, ITT and PP SR rate were 56% and 59%, respectively. No clinical or laboratory factors predictive of SR were identified. In arm B patients the serum concentrations of rituximab levels did not correlate with the rate of response. Twelve SR patients of arm A, 27 of arm B and 19 of salvage therapy group were systematically followed up beyond month 6 for a median period of observation of 18 months (range 10–34 months). The rate of SR loss (platelets < 50 × 109/L) in these three groups was 25 % (3/12), 11% (3/27) and 10.5% (2/19). The safety profile was good with no substantial difference between the two arms of randomization. No patient died during the study period.Conclusion. The results of this study indicate that the association of dexamethasone plus rituximab improves patients outcome without worsening of the safety profile. This effect is characterized by prolongation of SR and reduction in relapse rate. The long period of relapse free survival registered in some patients suggests a possible curative effect. This treatment can be offered as an option before splenectomy, particularly in those patients where the surgical option is not well accepted or have higher risk of complications.

The Addition of Rituximab Eliminates the Negative Prognostic Impact of PMBCL Compared to DLBCL in Young Patients with CD20-Positive Aggressive Lymphomas Receiving a CHOP-Like Chemotherapy: Results of a Subgroup Analysis of the Mabthera International Trial Group (MInT) Study

PMBCL is considered to be a distinct entity among diffuse large B-cell lymphoma (DLBCL). The optimal therapy is still matter of debate and the impact of the addition of rituximab to conventional chemotherapy is unknown. The aim of this subgroup analysis of the MInT study was to evaluate the effect of rituximab in PMBCL in comparison to other DLBCL with mediastinal involvement (mDLBCL). Eligible for the MInT study (Lancet Oncol 2006; 7: 379–91) were patients aged 18–60 years with DLBCL who had 0–1 risk factors according to age-adjusted International Prognostic Index (IPI), stage II-IV disease, or stage I disease with bulk. Patients were randomly assigned to six cycles CHOP-like chemotherapy regimens with or without rituximab. Consolidating radiotherapy (30–40 Gy) was given to sites of primary bulky disease.Results: Of 824 patients enrolled, 87 had PMBCL and 139 mDLBCL according to nationally centralized hematopathologist review. 44 patients (51%) with PMBCL and 65 patients (47%) with mDLBCL were randomized to the rituximab arm. The subsets were balanced for IPI, but patients with PMBCL were younger (median age 35 vs 43 years); showed more frequently an elevated LDH (63% vs 33%), stage I/II disease (92% vs 65%) and bulky disease (85% vs 60%); and received more often mediastinal radiotherapy (69% vs 37%) compared with mDLBCL. Rituximab increased the rates of complete remission or complete remission unconfirmed (CR/CRu) in both subsets although this was statistically significant only for PMBCL (see Table). This was mainly due to the fact that in both subsets rituximab virtually eliminated progressive disease (PD) under primary treatment, whereas without rituximab, PD tended to be more frequent in PMBCL than in mDLBCL (24% vs 11%, p=0.09). With a median observation time of 37 months (range 0–59), estimated 3-year event-free-survival (EFS) was improved by rituximab for PMBCL (78% vs 52%, p=0.012), mDLBCL (74% vs 59%, p=0.130), and all other DLBCL (n=597, 80% vs 60%, p<0.0001). Rituximab also improved progression-free-survival (PFS) of PMBCL, but not of mDLBCL (Table). This could be explained in part by the favorable outcome of mDLBCL compared to PMBCL in the chemotherapy-only arm (3-year PFS 77% vs 64%, p=0.08). In both subsets, the overall survival (OS) benefit observed with rituximab did not reach statistical significance (Table). Multivariable cox regression models (adjusting for treatment arm; IPI; etoposide use (CHOEP21); bulky disease; histology (PBMCL vs mDLBCL); and the interactions between histology and treatment arm, and histology and IPI, respectively) identified rituximab as a strong prognostic factor and a trend to an interaction between histology and treatment arm for the outcome of a patient.Conclusion: In young patients with PMBCL, rituximab added to 6 cycles of CHOP-like chemotherapy increases response rate, EFS, and PFS to the same extent as in other DLBCL, thereby eliminating the outcome disadvantage of PMBCL observed with CHOP-like chemotherapy alone.PMBCLRituximabCR/CRuPD3y-EFS3y-PFS3y-OSNo54% (38%–70%)24% (11%–38%)52% (35%–66%)64% (46%–77%)78% (61%–88%)Yes80% (68%–92%)3% (0%–7%)78% (61%–88%)88% (70%–95%)89% (71%–96%)P-value0.030.0060.0120.0060.16mDLBCLRituximabCR/CruPD3y-EFS3y-PFS3y-OSNo67% (55%–78%)11% (3%–18%)59% (46%–70%)77% (64%–86%)89% (79%–95%)Yes81% (71%–91%)2% (0%–5%)74% (60%–83%)81% (68%–89%)92% (79%–97%)P-value0.10.070.130.710.47

High Numbers of Tumor-Associated Macrophages Have an Adverse Prognostic Value That Can Be Circumvented by Rituximab in Patients With Follicular Lymphoma Enrolled Onto the GELA-GOELAMS FL-2000 Trial

High amounts of intratumoral macrophages have been shown to correlate with poor prognosis in patients with follicular lymphoma (FL) treated with chemotherapy without rituximab. We tried to establish whether intratumoral macrophage count (MC) definitely is able to predict the outcome of FL patients in the rituximab era. We analyzed immunohistochemical CD68 expression in 194 FL patients from the FL-2000 trial, randomly assigned to receive cyclophosphamide, doxorubicin, etoposide, prednisolone, and interferon (CHVP-I) or rituximab plus CHVP-I. Immunohistochemistry was performed on paraffin sections using anti-CD68 KP1 antibody, and stained macrophages were scored on high-power field (hpf) in either intrafollicular (IF) or extrafollicular (EF) areas. For IF MC, the best cutoff point was estimated at 10 macrophages/hpf. Low IF MC was significantly associated with a better event-free survival (EFS; P = .011). However, this effect was observed only in the CHVP-I arm (P = .012) and not in the rituximab plus CHVP-I arm. Using a cutoff of 15 IF MC, we found no significant association with EFS. For EF MC, fewer than 22 macrophages/hpf were associated with better EFS in the CHVP-I arm (P = .02) but not in the rituximab plus CHVP-I arm. These results show that MC can predict outcome of FL patients and that rituximab is able to circumvent the unfavorable outcome associated with high MC.

A Prospective Randomized Study of Rituximab and Dexamethasone vs Dexamethasone Alone in ITP.

Previous uncontrolled studies have highlighted the potential activity of Rituximab in patients with idiopathic thrombocytopenic purpura (ITP) relapsed or refractory to standard treatments. To better address this effect, a prospective randomized, multicenter, phase III study comparing treatment with Dexamethasone alone (arm A) vs Dexamethasone plus Rituximab (arm B) was started in July 2005 for adult patients with ITP according to the ASH guidelines. Main inclusion criteria were: age ≥ 18 years, untreated ITP, platelet (PLT) count ≤ 20 x109/L, HIV- HCV-HbsAg negativity, informed consent. Patients randomized to arm A received a single course of Dexamethasone 40 mg po on days +1, +2, +3, +4, while patients randomized to arm B received Dexamethasone (as in arm A) in association with Rituximab 375 mg/m2 iv on days +7, +14, +21, +28. Patients in arm A who failed to achieve a sustained response (SR) could be rescued with arm B treatment. The primary objective of the study was to compare SR, i.e. PLT ≥ 50 x 109/L at month + 6 of treatment. The secondary objectives were: the initial overall (OR= PLT ≥ 50 x109/L) and complete response (CR= PLT ≥ 100 x 109/L) by day 30 after starting treatment, respectively; the toxic profile. The statistical plan considered three interim analyses, after the first 50, 100 and 150 enrolled patients, with an estimated sample size of 198 patients (99 per arm). Table 1 summarizes the main demographic data and the results of efficacy and toxicity according to an intention to treat analysis of the first interim analysis. The toxic profile was characterized by only grade 3 adverse events (AE); no patient died during the study period. 16 patients of arm A were rescued with arm B. For this group SR was 81% and no patient experienced SAE or ≥ grade 3 AE. In accordance with the initial statistical plan of the study, which stated that patients' recruitment would ceased if a ≥ 50% difference in sustained response was demonstrated, enrolment has been stopped in June 2007 with a total number of 103 randomized patients. This preliminary report indicates a significantly higher SR for arm B of treatment with no difference in toxicity profile. A final report will be prepared when the results on the entire study group will be available.Table 1TherapyArm AArm BStatisticsPatients2426Male/female11/1310/16p = NSAge (median ± SD)54.54 ± 18.7848.65 ± 15.10p = NSInitial OR15 (62.5%)18 (69%)p = NSInitial CR10 (42%)16 (61%)p = NSSR7 (29%)21 (81%)p = 0.0001SAE or grade 3 AE3 (12.5%)2 (8%)p = NS

Rituximab in patients with rheumatoid arthritis: systematic review

Biologic treatments are newly used in rheumatoid arthritis. Three tumornecrosis factor alfa (TNF-alpha) inhibitors--adalimumab, etanercept and infliximab--have been licensed for rheumatoid arthritis in Hungary. B-cell targeted treatment with rituximab is the next biologic treatment. Rituximab was used earlier for the treatment of non-Hodgkin's lymphoma. Rituximab was registered to be used in patients with rheumatoid arthritis who have had an inadequate response or an intolerance to one or more TNF-alpha blocking agents. Systematic review in the literature of efficacy of rituximab in rheumatoid arthritis. To assess the efficacy and safety of rituximab treatment in patients with rheumatoid arthritis. MEDLINE and Cochrane database were searched for randomized controlled trials with rituximab in rheumatoid arthritis. A meta-analysis of trial data was conducted. Three randomized controlled trials were identified including 1145 patients. 54% of patients with inadequate response to TNF-alfa inhibitors and severe disease-activity have reached American College of Rheumatology 20 criteria. This ratio is larger with 33% (95% CI, 25-41%) than without treatment, and patients have almost five times (relative risk = 4.77 95% CI, 3.12-7.31) chance to improve. Functional status represented by Health Assessment Questionnaire score improves significantly (p < 0.001) in rituximab arms (-0.4 scores) compared with placebo arms (-0.1 scores). EULAR moderate and good responses in the rituximab group were significant (p < 0.00001) compared with the placebo group, rate difference is 38% (95% CI, 32-44%). Rituximab improves also radiological symptoms of rheumatoid arthritis. New therapeutic options, rituximab is efficacious in patients with rheumatoid arthritis. Rituximab can improve symptoms of patients with inadequate response to or intolerance of TNF-alpha inhibitors.

CEOP-21 Versus CEOP-14 Chemotherapy With or Without Rituximab for the First-Line Treatment of Patients With Aggressive Lymphomas: Results of the HE22A99 Trial of the Hellenic Cooperative Oncology Group

In this study we investigated whether administering CEOP (cyclophosphamide, epirubicin, vincristine [Oncovin], and prednisone) every 2 weeks (CEOP-14) instead of every 3 weeks (the standard CEOP-21 regimen) improves outcomes in patients with previously untreated aggressive lymphomas. In a secondary analysis we evaluated the impact of adding rituximab to CEOP-14/CEOP-21 chemotherapy. The trial opened in March 1999, and patients were randomly assigned to either CEOP-14 or CEOP-21. All patients enrolled from May 2002 onward received rituximab with each chemotherapy cycle, and those attaining a complete response received rituximab consolidation. Complete and overall response rates in the CEOP-21 +/- rituximab (N = 114) and CEOP-14 +/- rituximab (N = 103) arms were similar, as were the overall survival (P = 0.769) and time to progression distributions (P = 0.969). Rituximab was shown to have a beneficial effect both on the overall survival and on the time to progression. Thus far, no significant improvement in outcome has been demonstrated with CEOP-14 +/- rituximab versus CEOP-21 +/- rituximab. However, with addition of rituximab to CEOP-21/CEOP-14, significant improvements in time to progression and overall survival were achieved.

Six vs. Eight Cycles of Bi-Weekly CHOP-14 with or without Rituximab for Elderly Patients with Diffuse Large B-Cell Lymphoma (DLBCL): Results of the Completed RICOVER-60 Trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL).

Interval reduction from 3 (CHOP-21) to 2 weeks (CHOP-14; Pfreundschuh et al., Blood, 2004) and the addition of rituximab to CHOP-21 (R-CHOP-21; Coiffier et al., NEJM, 2002) improved outcome in elderly patients with DLBCL to a similar extent compared to CHOP-21. In the RICOVER-60 trial, elderly patients (61–80 years) were randomized to receive 6 or 8 cycles of CHOP-14 with or without rituximab given on days 1, 15, 29, 43, 57, 71, 85, and 99. Radiotherapy was planned to sites of initial bulk and/or extranodal involvement. Between 07/2000 and 06/2005, 1222 patients with CD20+ DLBCL and informed consent were recruited and evaluable (median age 68 years; IPI=1: 30%, IPI=2: 28%; IPI=3: 26%; IPI=4,5: 16%). The primary endpoint was event-free survival (EFS) with events defined as additional therapy, failure to achieve complete remission, progressive disease, relapse, or death. As by intention to treat, the 3-year EFS rate was 47% after 6×CHOP-14 (n=307), 53% after 8×CHOP-14 (n=305), 66% after 6×R-CHOP-14 (n=306), and 63% after 8×R-CHOP-14 (n=304). Regarding time-to-event data, we found a relevant interaction term (RR 1.4, p=0.068) between treatment contrasts and performd according to the protocol single-arm comparisons using 6×CHOP-14 without rituximab as the reference arm instead of a 2×2 factorial analysis. The p-values for the univariate log-rank tests of the improvement in EFS over 6×CHOP-14 were p=0.036 for 8×CHOP-14, and p<0.001 for 6×R-CHOP-14 and 8×R-CHOP-14, respectively. After a median observation time of 34.5 months, the estimated 3-year overall survival (OS) rates were 68% for 6×CHOP-14, 66% for 8×CHOP-14, 78% for 6×R-CHOP-14, and 72% for 8×R-CHOP-14. The p-values for the univariate log-rank tests of the OS improvement over 6×CHOP-14 were p=0.836 for 8×CHOP-14, p=0.018 for 6×R-CHOP-14 and p=0.260 for 8×R-CHOP-14. In a multivariate analysis using 6×CHOP-14 without rituximab as the reference and adjusting for the stratification variables (elevated LDH, advanced stage III&IV, ECOG performance state >1, bulky disease, >1 extranodal site, and age >70), both rituximab arms had a significantly improved EFS (6×R-CHOP-14: relative risk [RR]=0.51, p<0.001; 8×R-CHOP-14: RR 0.54, p<0.001; 8×CHOP14: RR 0.76, p=0.017). However, in the multivariate analysis for OS adjusting for the stratification variables, only the OS after 6×R-CHOP-14 (RR 0.63; p=0.003), but not after 8×R-CHOP-14 (RR=0.78; p=0.102) was significantly better than the OS after 6×CHOP-14. In summary, only 6 cycles of R-CHOP-14 significantly improved both EFS and OS over 6×CHOP-14, while 8×R-CHOP-14 did so only with respect to EFS. The reasons for the less favorable OS after 8×R-CHOP-14 compared to 6×R-CHOP-14 will be analyzed and discussed. The results after 6 cycles of R-CHOP-14 in this largest randomized trial of DLBLC performed to date are the best reported for elderly patients with CD20+ DLBCL. 6×R-CHOP-14 should be considered as reference standard in future trials for elderly patients with DLBCL.

Rituximab (Mabthera) Improves the Treatment Results of DHAP-VIM-DHAP and ASCT in Relapsed/Progressive Aggressive CD20+ NHL. A Prospective Randomized HOVON Trial.

A total of 239 patients with relapsed/progressive aggressive CD20+ NHL after/during adriamycin containing regimens, were recruited to the randomized HOVON-44 trial comparing DHAP-VIM-DHAP followed by BEAM and autologous stem cell re-infusion (ASCT)(“DHAP-arm”) with DHAP-VIM-DHAP in conjunction with Rituximab (375 mg/m2) and ASCT (“R-DHAP arm”). Of the included patients, 202 were evaluable and randomized to the DHAP arm (n=101) or R-DHAP arm (n=101). Only patients with CR/PR after two courses of intensive chemotherapy were eligible for ASCT. Patients were well balanced for risk factors. In both arms the majority of patients had not been exposed to Rituximab during first line treatment. As of July 2006, median follow-up of all patients still alive is 24.5 months. After two courses of chemotherapy PR/CR was obtained in 49 % of the patients in the DHAP arm and 77% in the R-DHAP arm (p=<.01;intention to treat analysis). Post-transplantation PR/CR was obtained in 41% and 58% of the patients respectively (p=.40). A significant difference between both arms was observed for failure free survival (FFS), disease free survival (DFS) and overall survival (OS) in favor of the Rituximab arm (p<.05, table 1). The less pronounced difference in OS between both arms is most likely due to the fact that non-responding or relapsing patients in the DHAP arm received salvage treatment with a Rituximab containing regimen. Additionally, a subgroup analysis was performed according to type of response to first-line treatment:1) Response duration more than 3 months (n=138); 2) Progression or response duration less than 3 months (n=64). Within both subgroups, the hazard ratio's for the endpoints were of equal magnitude (.40–.60), indicating that the beneficial effect of Rituximab existed in both subgroups. In conclusion these results demonstrate that the addition of Rituximab to second line of chemotherapy followed by ASCT results in a significant improved FFS, DFS, and OS in patients with relapsed/progressive aggressive CD20+ NHL.Table 1FFSDFSOSDHAP-arm*21%46%48%R-DHAP arm*52%82%62%Hazard ratio.40.32.61p-value log rank test<0.0010.0030.03*: 2 years estimate