Rituximab Retreatment Research Articles

FRI0334 Safety of rituximab for remission maintenance in relapsing anca–associated vasculitis: repeat cycles on clinical relapse are associated with low rates of hypogammaglobulinaemia

BackgroundRituximab is effective in ANCA-associated vasculitis (AAV). Since relapse often occurs after an initial response, either fixed-interval rituximab re-treatment or re-treatment-at-relapse is used to maintain long term response. Attrition of...

FRI0338 Efficacy and safety of rituximab retreatment in refractory systemic juvenile idiopathic arthritis

BackgroundChimeric monoclonal anti-CD20 B-cell antibody (rituximab) is promising drug for the treatment of systemic Juvenile Idiopathic Arthritis (SJIA) refractory to immunosuppressive drugs and TNFα-blockers.Objectivesevaluate clinical efficacy and safety of rituximab...

THU0090 Safety and efficacy of atacicept in combination with rituximab in patients with rheumatoid arthritis: Results from the atacicept for reduction of signs and symptoms in rheumatoid arthritis trial (III)

BackgroundAtacicept neutralizes the B cell maturation/survival factors BLyS and APRIL and has been investigated in autoimmune diseases.ObjectivesThis Phase II, randomized, double-blind, placebo-controlled, multicenter trial assessed safety and efficacy of atacicept...

Evaluation of low-dose rituximab for the retreatment of patients with active rheumatoid arthritis: a non-inferiority randomised controlled trial

BackgroundThe licensed dose of rituximab in rheumatoid arthritis (RA) is two doses of 1000 mg given 2 weeks apart. A lower dose has never been specifically studied in patients with...

Five-Year Data from the REFLEX Study: A Different Interpretation

To the Editor: I read the 5-year extension data from the REFLEX study1 with interest but found the title of the paper — as well as its conclusion — misleading. The authors conclude that rituximab (RTX) re-treatment is associated with maintained or improved efficacy based on clinical responses measured after each of up to 5 courses of RTX. However, there is a fairly pronounced dropout of patients after each course, such that fewer than 20% of … Address correspondence to Dr. Abeles; E-mail: aabeles{at}uchc.edu

Safety of Rituximab in Combination with Other Biologic Disease-modifying Antirheumatic Drugs in Rheumatoid Arthritis: An Open-label Study

To characterize the safety of rituximab (RTX) in combination with biologic disease-modifying antirheumatic drugs (DMARD) in patients with rheumatoid arthritis (RA). We did an open-label study of the safety and efficacy of RTX in adult patients with active RA and an inadequate response to ≥ 1 biologic for ≥ 12 weeks (stable dose ≥ 4 weeks). RTX (2 × 500 mg) was added to patients' current biologic and nonbiologic DMARD treatment. After 24 weeks, patients with 28-joint Disease Activity Score ≥ 2.6 were eligible for RTX retreatment. The primary endpoint was the proportion of patients developing a serious adverse event (SAE) within 24 weeks of initiating RTX. Patients (n = 176) received RTX with 18 different biologic/DMARD combinations. Adalimumab alone (n = 46; 26.1%) or etanercept alone (n = 37; 21.0%) plus RTX were the most common combinations. Overall, 90.9% and 76.1% of patients completed 24 and 48 weeks, respectively; 147 patients (83.5%) received a second course of RTX. Over 24 weeks, 9.1% of patients reported SAE (24.3 events/100 patient-yrs, 95% CI 15.5-38.1). The SAE rate was similar over 48 weeks (22.4 events/100 patient-yrs, 95% CI 15.9-31.5). Four serious infections were reported over 48 weeks (2.7 events/100 patient-yrs, 95% CI 1.0-7.2). No SAE occurred within 24 h of any RTX infusion. Efficacy responses improved numerically at Week 48 compared with Week 24. The overall safety profile of RTX in combination with 1 other biologic was consistent with that previously reported for RTX plus methotrexate or other nonbiologic DMARD. (Clinicaltrials.gov NCT00443651).

Quality of Life Results From Eastern Cooperative Oncology Group Protocol E4402 (RESORT): A Randomized Phase III Study Comparing Two Different Rituximab Dosing Strategies for Indolent Non-Hodgkin's Lymphoma

AbstractAbstract 235 Background:The RESORT trial (E4402) found comparable time to treatment failure (TTTF) and disease-related outcomes in previously untreated, indolent, follicular lymphoma randomized to maintenance rituximab (MR) versus rituximab retreatment (RR), and possible benefit of MR for patients with non-follicular lymphoma. The effects of MR versus RR on patient anxiety and health-related quality of life has not previously been examined. Methods:Pt received R 375 mg/m2 weekly × 4 and responders were randomized to MR (single dose R q 3 mo) or RR (R weekly × 4 at disease progression). Each strategy was continued until treatment failure. Participants enrolled after 5/2005 completed a patient-reported outcomes (PRO) assessment. Patient preferences regarding treatment were measured at randomization using 4 patient self-report items developed for this trial. These 4 items asked patients to rate the extent to which medical visits and cancer treatment reduces their anxiety and increases perceived control, and the extent to which they prefer to avoid medical care due to an increase in anxiety in response to reminders of illness. Participants were categorized based on their responses as using “active coping” (medical care decreases anxiety) or “avoidant coping” (prefer to avoid medical care). Participants completed PRO assessment following R induction at randomization, 3, 6, 12, 24, 36, and 48 months post-randomization, and at R failure. PRO assessment included standardized, validated questionnaires to measure general anxiety and depression (Hospital Anxiety and Depression Scale, HADS), post-traumatic stress-type anxiety (Impact of Events Scale-Revised, IES-R), and health-related quality of life (Functional Assessment of Cancer Therapy–General, FACT-G). Individual items were selected from existing measures or were developed for this trial to assess illness-specific anxiety about the future (Illness Impact). Primary PRO analysis compared change scores from randomization-12 months between MR and RR treatment arms. Differences between participants categorized as using active or avoidant coping were also examined. Results:253 patients (92% of E4402 randomized sample) completed PROs at randomization. 125 patients were randomized to MR and 128 were randomized to RR. Demographic and disease characteristics were comparable between arms. Median age 60 years, 54% female, 95% White. All patients PS 0–1; 83% follicular lymphoma, 17% non-follicular. The study had 80% power to detect an effect size of 0.4 for the primary endpoint (change scores randomization to 12 months). There were no statistically significant differences between MR and RR on (1) any PRO measure and (2) PRO change scores from randomization to 12 month follow-up (p=NS). Figure 1 illustrates HADS Anxiety scores and Figure 2 shows FACT-G scores from randomization-48 months. The proportion of participants exceeding established clinical cut-off scores on the HADS Anxiety and IES-R did not differ between MR and RR. At randomization, 70% of participants were categorized as using an avoidant coping style and 30% as using active coping. Among participants using avoidant coping, 6–10% exceeded HADS Anxiety clinical cut-off at randomization, 3, 6, and 12 month assessments, and 16% at R failure. A lower proportion of those using active coping (0–3%) reported clinically significant anxiety at all time points (p<0.05). A higher proportion of avoidant coping patients exceeded IES-R clinical cut-off (10–18%), indicating greater post-traumatic anxiety than active coping patients (34%; p<0.01). Conclusion:In previously untreated, indolent, non-Hodgkin’s lymphoma, MR and RR are comparable with regard to patient-reported anxiety, post-traumatic anxiety, illness-specific anxiety about the future, and overall HRQL. MR did not result in reduced anxiety or better HRQL compared to RR, even among patients who report that medical visits and ongoing treatment reduce anxiety (“active coping”). RR did not result in lower anxiety or better HRQL among patients who reported a preference to avoid medical visits due to increased anxiety (“avoidant coping”). Administration of R q 3 months was not associated with functional improvements or detriments to HRQL, indicating R is well-tolerated. For MR and RR, avoidant coping was associated with a higher likelihood of clinically significant general anxiety and post-traumatic anxiety. [Display omitted] [Display omitted] Disclosures:Williams:Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding. Horning:Genentech: Employment. Kahl:Genentech: Consultancy, Research Funding; Roche: Consultancy.

Phase II Safety and Efficacy Study of CT-011, a Humanized Anti-PD-1 Monoclonal Antibody, in Combination with Rituximab in Patients with Relapsed Follicular Lymphoma

AbstractAbstract 793 Background:Follicular lymphoma (FL) is one of the most immune-responsive of all cancers. However, immunosuppressive mechanisms in the tumor microenvironment may impair optimal antitumor immune responses. Expression of programmed death (PD)-1, a coinhibitory receptor, is markedly increased on intratumoral T cells in FL and is associated with impaired T-cell function. CT-011 (pidilizumab), a humanized anti-PD-1 monoclonal antibody, blocks the PD-1/PD-ligand pathway, and can enhance the function of antitumor T cells and NK cells. Rituximab, the monoclonal anti-CD20 antibody, acts in part via activation of NK cell-mediated antibody-dependent cellular cytotoxicity. Therefore, the combination of CT-011 and rituximab may have additive and/or synergistic effects via activation of both innate (NK cells) and adaptive (T cells) arms of the immune system and enhance clinical efficacy without increasing toxicity. We conducted a single arm phase II trial to determine the safety and efficacy of CT-011 and rituximab in patients (pts) with relapsed FL. Methods:Pts with rituximab-sensitive, grade 1–2 FL relapsed after 1–4 prior therapies with measurable disease, adequate organ function, and absolute lymphocyte count of ≥ 0.6×109/L were eligible for enrollment. Pts with HIV, hepatitis B or C, and history of autoimmune diseases or allogeneic stem cell transplantation were excluded. CT-011 was dosed at 3 mg/kg IV every 4 weeks (wks) for 4 infusions and rituximab was dosed at 375 mg/m2 IV weekly for 4 wks starting 2 wks after the first infusion of CT-011. Pts with complete response (CR), partial response (PR), or stable disease (SD) received 8 additional optional infusions of CT-011 every 4 wks (for a total of 12). Pts were evaluated for response by CT scans and/or PET after 2 and 4 infusions of CT-011 and every 3 months (mo) thereafter for up to 2 yrs. Bone marrow biopsy was performed to confirm CR when appropriate. Blood and tumor samples were collected to assess the effect of CT-011 on immune cells and are reported separately. The primary objective was to determine the overall response rate (ORR). The secondary objectives were to determine the safety and toxicity, CR rate, progression-free survival (PFS), effect of CT-011 on T and NK cells, and to evaluate the immunogenicity and pharmacokinetics of CT-011. The combination was estimated to induce an ORR of at least 60% as compared to an ORR of 40% with rituximab retreatment (Davis et al, J Clin Oncol, 2000). A sample size of 30 was estimated to be adequate for this purpose. Results:Of the 30 pts enrolled and treated on the study, one pt was not evaluable for efficacy analysis. Characteristics of the 29 evaluable pts were: median age 61 years (range, 35–79); 57% male; FLIPI low-41%, int-24%, high-35%, FLIPI2 low-24%, int-48%, high-28%; and median prior therapies 1 (range, 1–4). All pts previously received rituximab, median number of prior doses was 6 (range, 2–22), 69% had prior chemotherapy or chemoimmunotherapy, 41% combination biologic therapy, 21% maintenance rituximab, 7% radioimmunotherapy, and 3% single agent rituximab. The median number of CT-011 infusions administered was 10 (range, 1 – 12). The treatment was well tolerated with no therapy-related grade 3/4 toxicities, and no pt discontinued therapy due to toxicity. Of 29 pts eligible for efficacy analysis, 19 pts had an objective response for an ORR of 66%. CR was observed in 15 (52%) and PR in 4 (14%). Altogether, 25 (86%) pts had measurable tumor regression. Median time to response was 88 days. Of note, 17% of pts achieved initial response >3 mo from first treatment. After a median follow up of 14 mo, median PFS was 21.1 mo, and was not reached for the 19 responders or the 25 pts with measurable tumor regression. Clinical response was not significantly associated with FLIPI, FLIPI2, prior chemotherapy, number of prior rituximab doses, or duration of response to prior therapy (p>0.05). However, PFS was significantly associated with both FLIPI (median PFS for low/int versus high, not reached (NR) versus 12.65 mo; p=0.0056) and FLIPI2 (median PFS for low/int versus high, NR versus 13.47 mo; p=0.0344). Conclusions:The combination of CT-011 (pidilizumab) and rituximab was active and well tolerated in pts with relapsed FL. The ORR of 66% and CR rate of 52% compare favorably with the previously reported ORR of 40% and CR rate of 11% with rituximab retreatment in relapsed FL. These data support further evaluation of PD-1 targeted therapy in FL. Disclosures:Fanale:Genetech: Research Funding. Rotem-Yehudar:CureTech Ltd: Employment, Research Funding.

Rituximab for remission maintenance in relapsing antineutrophil cytoplasmic antibody–associated vasculitis

Rituximab is effective induction therapy in refractory or relapsing antineutrophil cytoplasmic antibody-associated vasculitis (AAV). However, further relapse is common, and maintenance strategies are required. The aim of this study was to reduce relapse rates using a fixed-interval rituximab re-treatment protocol. Retrospective, standardized collection of data from sequential patients receiving rituximab for refractory or relapsing AAV at a single center was studied. Group A patients (n = 28) received rituximab induction therapy (4 infusions of 375 mg/m(2) or 2 infusions 1 gm) and further rituximab at the time of subsequent relapse. Group B patients (n = 45) received routine rituximab re-treatment for 2 years: 2 doses of 1 gm each for remission induction, then 1 gm every 6 months (total of 6 gm). Group C patients (n = 19) comprised patients in group A who subsequently relapsed and began routine re-treatment for 2 years. Response (complete/partial remission) occurred in 26 of the 28 patients (93%) in group A, 43 of the 45 patients (96%) in group B, and 18 of the 19 patients (95%) in group C. At 2 years, relapses had occurred in 19 of 26 patients (73%) in group A, 5 of 43 (12%) in group B (P < 0.001), and 2 of 18 (11%) in group C (P < 0.001). At the last followup (median of 44 months), relapses had occurred in 85% of those in group A (22 of 26), 26% of those in group B (11 of 43; P < 0.001), and 56% of those in group C (10 of 18; P = 0.001). Glucocorticoid dosages were decreased and immunosuppression therapy was withdrawn in the majority of patients. Routine rituximab re-treatment was well tolerated, and no new safety issues were identified. Two-year, fixed-interval rituximab re-treatment was associated with a reduction in relapse rates during the re-treatment period and a more prolonged period of remission during subsequent followup. In the absence of biomarkers that accurately predict relapse, routine rituximab re-treatment may be an effective strategy for remission maintenance in patients with refractory and relapsing AAV.

Rituximab maintenance versus retreatment in follicular lymphoma

Follicular lymphoma (FL) is the most common type of indolent non-Hodgkin lymphoma. Although the introduction of the anti-CD20 monoclonal antibody rituximab has represented a major breakthrough, FL remains incurable with standard chemoimmunotherapies. The goals of therapy in symptomatic FL patients include the following: obtaining high response rates, extending the duration of remission, prolongation of survival and improving quality of life, while minimizing adverse events. To extend remission duration and possibly survival outcomes, maintenance therapy with rituximab has been shown to be effective in both frontline and relapsed/refractory settings. However, the optimal timing, schedule and length of maintenance therapy are controversial. Herein, we review the current data for maintenance rituximab in FL, discuss the current controversies for this modality, attempt to define its role relative to the more conservative retreatment approach and provide practical recommendations for its clinical use.

Rituximab maintenance for relapsed refractory thrombotic thrombocytopenic purpura

Rituximab, an anti-CD20 chimeric monoclonal antibody, has been used successfully to treat patients with relapsed or refractory thrombotic thrombocytopenic purpura (TTP); however, the optimal dose and frequency and the role of rituximab maintenance remain uncertain. We describe a 45-year-old woman with chronic relapsing immune thrombocytopenia who responded to rituximab retreatment administered in four doses over the course of 12 months. Previously, she had received four doses of rituximab and sustained a remission for 19 months. During her latest TTP relapse, multiple treatments were administered including rituximab retreatment. After the first dose (375 mg/m2), she developed serum sickness requiring further doses to be deferred. Three subsequent doses were administered at 4-month intervals over the course of 12 months. ADAMTS13 activity was measured by von Willebrand factor (VWF) digestion. ADAMTS13 inhibition was measured by a modification of the VWF digestion assay and anti-ADAMTS13 antibodies were measured by enzyme-linked immunoassay (enzyme-linked immunosorbent assay, American Diagnostica). Clinical and laboratory remission were achieved after one dose of rituximab, with normalization of ADAMTS13 activity and disappearance of ADAMTS13 inhibitor. Three subsequent doses of rituximab were given without incident and the patient remained in remission after 3.5 years of follow-up (2.5 years since her last dose of rituximab). Maintenance dosing of rituximab should be considered in some patients with relapsing TTP.

Blood memory B cells are disturbed and predict the response to rituximab in patients with rheumatoid arthritis

To examine blood B cell subsets in patients with rheumatoid arthritis (RA) prior to B cell depletion therapy and to assess their potential as predictors of clinical response to rituximab (RTX). Blood B cell subsets were assessed by flow cytometry in 208 RA patients included in an RTX retreatment study (assessed prior to RTX treatment) and in 47 age-matched controls. Expression of BAFF receptor (BAFF-R) on B cells and serum B cell biomarkers was also measured. B cell subsets and BAFF-R expression were compared between RA patient and control populations. Univariate and multivariate analyses were performed to identify baseline factors associated with a European League Against Rheumatism response 24 weeks after 1 cycle of RTX. Mean ± SD counts of both CD27- naive and CD27+ memory B cells were decreased in RA patients (188.6 ± 121.4/mm(3)) compared with controls (257.3 ± 154.1/mm(3)) (P = 0.001) and were partially restored in patients treated with methotrexate (MTX) plus anti-tumor necrosis factor compared with patients treated with MTX alone. Within the CD27+ memory B cells, the CD27+IgD- switched memory subtype was selectively decreased, irrespective of treatment. The frequency of CD27+ memory B cells correlated inversely with levels of several B cell activation biomarkers in RA. Serum BAFF level and BAFF-R expression was comparable in RA patients and controls. A low baseline CD27+ memory B cell frequency was associated with a greater clinical response to RTX (odds ratio 0.97 [95% confidence interval 0.95-0.99], P = 0.0015). In B cell depletion therapy-naive RA patients, a low frequency of CD27+ memory B cells correlated with levels of serum B cell activation biomarkers and may predict response to RTX. These results suggest that low memory B cell frequency may be indicative of a B cell-driven RA subtype that is more sensitive to B cell depletion therapy.

Results of Eastern Cooperative Oncology Group Protocol E4402 (RESORT): A Randomized Phase III Study Comparing Two Different Rituximab Dosing Strategies for Low Tumor Burden Follicular Lymphoma

Abstract LBA-6 Background:Optimal management for low tumor burden (LTB) follicular lymphoma (FL) in the rituximab (R) era is uncertain. Historical data with watch and wait (W & W) approaches are associated with an average of 3 years to initiation of chemotherapy. We hypothesized that rituximab could delay the need for chemotherapy and that maintenance rituximab (MR) would provide disease control superior to rituximab retreatment (RR) at progression. E4402 is a randomized phase III study comparing MR and RR for patients (pt) with previously untreated, LTB (by GELF criteria) FL. Methods:Pt received R 375 mg/m2 weekly × 4 and responders were randomized to MR (single dose R q 3 mo) or RR (R weekly × 4 at disease progression). Each strategy was continued until treatment failure. The primary endpoint, time to treatment failure (TTTF), was defined as progression within 6 mo of last R, no response to R retreatment, initiation of alternative therapy, or inability to complete protocol therapy. Pt were evaluated every 3 mo, with restaging CT scans every 6 mo. The study had 81% power to detect a TTTF hazard ratio of 0.64 favoring MR. Secondary endpoints included time to first cytotoxic therapy (TTCT), quality of life (QOL) and safety. The ECOG Data Monitoring Committee recommended release of study results at a planned interim analysis in September 2011. Results:From 11/03 to 9/08, 384 with FL were enrolled. Complete or partial response was achieved in 274 pt (71%), who were then randomized to MR (n=140) or RR (n=134). Demographic features were similar in the two arms: median age 59 yr; PS 0–1 in all pt; and FLIPI low-risk (14.9 vs. 16.4%), intermediate-risk (46.3 vs. 42.9%) and high-risk (38.8 vs. 40.7%) for MR vs. RR, respectively. The mean number of R doses/pt (including the 4 induction doses) was 15.8 (range 5– 31) for MR and 4.5 (range 4–16) for RR. With a median follow-up of 3.8 yrs, TTTF was and 3.9 yr for MR vs. 3.6 yr for RR (p=NS, Fig 1). A detailed analysis of treatment failure, by type, will be presented. At 3 yrs, 95% of MR vs. 86% of RR pt (p=.027, Fig 2) remained free of cytotoxic therapy. Grade 3–4 hematologic and non-hematologic toxicities occurred in < 5% of pt; 1 death on study occurred in each Arm. At 12 months post randomization, there was no discernible difference in health related QOL and anxiety between the two arms. [Display omitted] Conclusions:In previously untreated, low tumor burden, follicular lymphoma, no difference in TTTF for MR vs. RR was observed. Notably, the time to initiation of cytotoxic therapy was delayed in both arms compared to historical W & W strategies with similarly defined LTB FL populations. MR was slightly superior to RR for TTCT but at a cost of 3x more R. MR did not improve QOL or anxiety. In summary, RR produces outcomes comparable to MR in this patient population. Disclosures:Kahl:Genentech: Consultancy; Roche: Consultancy. Williams:Genentech: Consultancy. Gascoyne:Roche: Consultancy; Genentech: Consultancy. Horning:Genentech: Employment, Equity Ownership.

Results of Eastern Cooperative Oncology Group Protocol E4402 (RESORT): A Randomized Phase III Study Comparing Two Different Rituximab Dosing Strategies for Low Tumor Burden Follicular Lymphoma

Abstract LBA-6 Background: Optimal management for low tumor burden (LTB) follicular lymphoma (FL) in the rituximab (R) era is uncertain. Historical data with watch and wait (W &amp; W) approaches are associated with an average of 3 years to initiation of chemotherapy. We hypothesized that rituximab could delay the need for chemotherapy and that maintenance rituximab (MR) would provide disease control superior to rituximab retreatment (RR) at progression. E4402 is a randomized phase III study comparing MR and RR for patients (pt) with previously untreated, LTB (by GELF criteria) FL. Methods: Pt received R 375 mg/m2 weekly × 4 and responders were randomized to MR (single dose R q 3 mo) or RR (R weekly × 4 at disease progression). Each strategy was continued until treatment failure. The primary endpoint, time to treatment failure (TTTF), was defined as progression within 6 mo of last R, no response to R retreatment, initiation of alternative therapy, or inability to complete protocol therapy. Pt were evaluated every 3 mo, with restaging CT scans every 6 mo. The study had 81% power to detect a TTTF hazard ratio of 0.64 favoring MR. Secondary endpoints included time to first cytotoxic therapy (TTCT), quality of life (QOL) and safety. The ECOG Data Monitoring Committee recommended release of study results at a planned interim analysis in September 2011. Results: From 11/03 to 9/08, 384 with FL were enrolled. Complete or partial response was achieved in 274 pt (71%), who were then randomized to MR (n=140) or RR (n=134). Demographic features were similar in the two arms: median age 59 yr; PS 0–1 in all pt; and FLIPI low-risk (14.9 vs. 16.4%), intermediate-risk (46.3 vs. 42.9%) and high-risk (38.8 vs. 40.7%) for MR vs. RR, respectively. The mean number of R doses/pt (including the 4 induction doses) was 15.8 (range 5– 31) for MR and 4.5 (range 4–16) for RR. With a median follow-up of 3.8 yrs, TTTF was and 3.9 yr for MR vs. 3.6 yr for RR (p=NS, Fig 1). A detailed analysis of treatment failure, by type, will be presented. At 3 yrs, 95% of MR vs. 86% of RR pt (p=.027, Fig 2) remained free of cytotoxic therapy. Grade 3–4 hematologic and non-hematologic toxicities occurred in &lt; 5% of pt; 1 death on study occurred in each Arm. At 12 months post randomization, there was no discernible difference in health related QOL and anxiety between the two arms. Conclusions: In previously untreated, low tumor burden, follicular lymphoma, no difference in TTTF for MR vs. RR was observed. Notably, the time to initiation of cytotoxic therapy was delayed in both arms compared to historical W &amp; W strategies with similarly defined LTB FL populations. MR was slightly superior to RR for TTCT but at a cost of 3x more R. MR did not improve QOL or anxiety. In summary, RR produces outcomes comparable to MR in this patient population. Disclosures: Kahl: Genentech: Consultancy; Roche: Consultancy. Williams:Genentech: Consultancy. Gascoyne:Roche: Consultancy; Genentech: Consultancy. Horning:Genentech: Employment, Equity Ownership.

Retreatment with rituximab based on a treatment-to-target approach provides better disease control than treatment as needed in patients with rheumatoid arthritis: a retrospective pooled analysis

Objective. To assess the efficacy and safety profiles of two different rituximab retreatment regimens in patients with RA.Methods. Four hundred and ninety-three RA patients with an inadequate response to MTX recruited into rituximab Phase II/III studies received further courses of open-label rituximab based on two approaches: (i) treatment to target (TT): patients assessed 24 weeks after each course and retreated if not in remission [DAS in 28 joints based on ESR (DAS-28-ESR) ≥ 2.6]; (ii) treatment as needed (PRN): patients retreated at the physician’s discretion ≥24 weeks following the first course and ≥16 weeks following further courses, if both swollen and tender joint counts were ≥8. All courses consisted of i.v. rituximab 2 × 1000 mg 2 weeks apart plus MTX. Observed data were analysed according to treatment strategy.Results. Multiple courses of rituximab maintained or improved responses irrespective of regimen. TT provided tighter control of disease activity with significantly greater improvements in DAS-28-ESR and lower HAQ-disability index scores vs PRN. TT resulted in significantly more patients achieving major clinical response. PRN resulted in recurrence of disease symptoms between courses, with TT significantly reducing the incidence of RA flares. Despite more frequent retreatment with TT compared with PRN, the rates of serious adverse events and serious infections were comparable between regimens.Conclusions. Retreatment with rituximab based on 24-week evaluations and to a target of DAS-28-ESR remission leads to improved efficacy and tighter control of disease activity compared with PRN without a compromised safety profile. TT may be the preferable rituximab treatment regimen for patients with RA.

Neurophysiological and clinical responses to rituximab in patients with anti-MAG polyneuropathy

Objectives Rituximab treatment has shown clinical improvement in anti-myelin associated glycoprotein (MAG) polyneuropathy. We analyzed scores of clinical scales and the most sensitive electrophysiological parameters before and after immunomodulating treatment with rituximab in a group of patients affected by anti-MAG demyelinating polyneuropathy. Methods Clinical scores, the percentage of CD20 B-lymphocytes, anti-MAG antibody titers and electrophysiological data in 7 patients with anti-MAG polyneuropathy were analyzed. The patients were examined before a cycle with rituximab, 6, 12 and 24 months after the end of the treatment. Two patients were treated with rituximab additional cycles and re-evaluated 48 months after the first treatment. Results There were no evident correlation between anti-MAG serum antibody titers or clinical scales and electrodiagnostic data. Significant decrease in the proportion of CD20 B-lymphocytes was observed. Significant anti-MAG antibodies titers reduction was detected after re-treatment. At follow-up, pinprik sensation and two point discrimination presented a significant improvement compared with the score before treatment. Conclusions In our patients, rituximab did not improve any electrophysiological data. No correlation with anti-MAG serum antibodies course was found. With rituximab only pin sensibility improved. Significance Rituximab re-treatment significantly reduces anti-MAG serum antibodies titers but improves only small fibers sensibility.

B cell activation biomarkers as predictive factors for the response to rituximab in rheumatoid arthritis: A six‐month, national, multicenter, open‐label study

To examine whether serum B cell markers can predict response to rituximab, a B cell-depleting monoclonal antibody, in patients with refractory rheumatoid arthritis (RA). This rituximab re-treatment dose study (SMART [eSsai MAbthera sur la dose de Re-Traitement]) involved 208 patients with refractory RA. Serum markers of B cell activation (anti-cyclic citrullinated peptide [anti-CCP] antibodies, rheumatoid factor [RF], serum IgG, IgA, and IgM levels, serum κ and λ free light chains, and serum BAFF) were assessed before the first rituximab cycle (1,000 mg on days 1 and 15). Univariate and multivariate analyses were performed to identify factors associated with a European League Against Rheumatism (EULAR) response at 24 weeks. There were 149 responders (72%). Two baseline factors were associated with a EULAR response at 24 weeks in multivariate analysis: the presence of anti-CCP antibodies or RF (odds ratio 3.5 [95% confidence interval 1.6-7.6]) and a serum IgG concentration above normal (odds ratio 2.11 [95% confidence interval 1.02-4.33]), with synergy between them (odds ratio 6.0 [95% confidence interval 2.2-16.2]). The presence of RF or anti-CCP antibodies and elevated IgG are 2 simple biomarkers that can be used routinely before therapy to predict response to rituximab in patients with refractory RA.

Treatment of severe uveitis associated with juvenile idiopathic arthritis with anti-CD20 monoclonal antibody (rituximab)

Rituximab (RTX), a chimeric mAb directed against the B-cell marker CD20, was investigated for its anti-inflammatory effect in treating refractory uveitis associated with JIA. Case series, retrospective multicentre. JIA patients with severe uveitis with vision-threatening complications (n = 10) and with insidious onset. All patients were treated with RTX for active uveitis refractory to topical and systemic CSs, immunosuppressives and at least one of the TNF-α inhibitors. All had active arthritis. Uveitis and arthritis course were assessed before and after RTX treatment. After one RTX cycle (mean follow-up 11 months, range 7-18 months), uveitis inactivity was achieved in seven oligoarthritis patients (ANA⁺, HLA-B27⁻) for a prolonged period of time (mean 7.5 months, range 6-9 months). Therefore, CSs and immunosuppression could be spared. In three of four patients responding to RTX, uveitis recurred thereafter, and RTX re-treatment led to inactivity again. In another three patients (ANA⁺ polyarthritis, n = 1; ANA⁺ HLA-B27⁺ oligo- or polyarthritis, n = 2) uveitis activity persisted after RTX therapy. In seven patients, arthritis improved or was inactive after RTX treatment (PedACR30/50/70). RTX may represent a rescue therapy option for severe JIA-associated uveitis refractory to CSs, immunosuppression and TNF-α inhibitors.

Effect of addition of rituximab to salvage chemotherapy on outcome of patients with diffuse large B-cell lymphoma relapsing after an autologous stem-cell transplantation

BackgroundWe have investigated if rituximab-based salvage regimens improve response rates and survival of patients with diffuse large B-cell lymphoma (DLBCL) relapsing after an autologous stem-cell transplantation (ASCT). Patients and methodsWe have retrospectively analyzed 82 patients with DLBCL who received salvage therapy for relapse or progression after ASCT. Patients were divided into two groups, according to whether rituximab-based salvage regimens were given (n = 42, ‘R-’ group) or not (n = 40, ‘R+’ group) after ASCT. ResultsPatients in the R+ group had better complete remission (CR) (55% versus 21.4%, P = 0.006) and overall response (OR) (75% versus 40.4%, P = 0.001) rates, and better 3-year event-free survival (EFS) (37% versus 9%, P = 0.002) and overall survival (OS) (50% versus 20%, P = 0.005) than patients in the R- group. Patients retreated with rituximab had better CR (42.9% versus 21.4%, P = 0.032) and OR (66.7% versus 40.4%, P = 0.019) rates, and better OS (36.2% versus 20% at 3 years, P = 0.05) and EFS (36.2% versus 9% at 3 years, P = 0.05) than patients who received chemotherapy alone at relapse after ASCT. ConclusionsThe addition of rituximab to salvage chemotherapy improves response rates and EFS in patients with relapsed DLBCL after ASCT. These patients may benefit from rituximab retreatment, although larger prospective studies are needed to confirm these results.

Swiss Consensus Statement: Recommendations for optimising re-treatment with MabThera® (rituximab) in rheumatoid arthritis

Rituximab is an effective treatment of rheumatoid arthritis (RA), which has been approved for the treatment of moderate to severe disease in patients with an inadequate response to anti-TNF therapies. Rituximab differs from other available biological agents for RA by way of its unique mode of action and unrivalled long dosing interval. The efficacy of rituximab subsides progressively over time and re-therapy is generally required to maintain long term disease control. The timing of re-treatment is currently not well established and varies widely in clinical practice. The present document is a concise recommendation regarding re-treatment with rituximab, based on validated outcomes such as the DAS28 and the EULAR response criteria. The recommendation was established through consensus between practitioners familiar with rituximab therapy in RA. Optimisation of the rituximab re-treatment schedule may improve patient outcomes and balance risks and benefits for the individual patient.