Multiple Courses Of Rituximab Research Articles

Long-Term Efficacy and Safety of Repeated Rituximab to Maintain Remission in Idiopathic Childhood Nephrotic Syndrome: An International Study.

Long-term outcomes after multiple courses of rituximab among children with frequently relapsing, steroid-dependent nephrotic syndrome (FRSDNS) are unknown. A retrospective cohort study at 16 pediatric nephrology centers from ten countries in Asia, Europe, and North America included children with FRSDNS who received two or more courses of rituximab. Primary outcomes were relapse-free survival and adverse events. A total of 346 children (age, 9.8 years; IQR, 6.6-13.5 years; 73% boys) received 1149 courses of rituximab. A total of 145, 83, 50, 28, 22, and 18 children received two, three, four, five, six, and seven or more courses, respectively. Median (IQR) follow-up was 5.9 (4.3-7.7) years. Relapse-free survival differed by treatment courses (clustered log-rank test P<0.001). Compared with the first course (10.0 months; 95% CI, 9.0 to 10.7 months), relapse-free period and relapse risk progressively improved after subsequent courses (12.0-16.0 months; HRadj, 0.03-0.13; 95% CI, 0.01 to 0.18; P<0.001). The duration of B-cell depletion remained similar with repeated treatments (6.1 months; 95% CI, 6.0 to 6.3 months). Adverse events were mostly mild; the most common adverse events were hypogammaglobulinemia (50.9%), infection (4.5%), and neutropenia (3.7%). Side effects did not increase with more treatment courses nor a higher cumulative dose. Only 78 of the 353 episodes of hypogammaglobulinemia were clinically significant. Younger age at presentation (2.8 versus 3.3 years; P=0.05), age at first rituximab treatment (8.0 versus 10.0 years; P=0.01), and history of steroid resistance (28% versus 18%; P=0.01) were associated with significant hypogammaglobulinemia. All 53 infective episodes resolved, except for one patient with hepatitis B infection and another with EBV infection. There were 42 episodes of neutropenia, associated with history of steroid resistance (30% versus 20%; P=0.04). Upon last follow-up, 332 children (96%) had normal kidney function. Children receiving repeated courses of rituximab for FRSDNS experience an improving clinical response. Side effects appear acceptable, but significant complications can occur. These findings support repeated rituximab use in FRSDNS.

POS-467 Long-term efficacy and safety of repeated rituximab therapy in children with frequently-relapsing, steroid-dependent nephrotic syndrome: an international multicentre study

Children with frequently-relapsing, steroid-dependent nephrotic syndrome (FRSDNS) often require multiple courses of rituximab. However, long-term effects are unknown. The aim of this study is to evaluate the long-term efficacy and safety in these children following repeated courses of rituximab.

Concomitant Secondary Peripheral T-cell Lymphoma with Therapy-related Chronic Myelomonocytic Leukemia in a Patient with History of High-grade Follicular Lymphoma

A secondary myeloid or lymphoid neoplasm is not infrequently associated with a primary tumor, solid or hematopoietic, post cytotoxic treatment or radiation. Concurrent secondary neoplasms derived from distinct myeloid and lymphoid cell origins are rare. It is not only a diagnostic challenge, but makes for difficult treatment management. We report a very rare occurrence in 63-year-old male with a history of high-grade follicular lymphoma who was treated with multiple courses of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP) and then developed a concurrent secondary peripheral T-cell lymphoma, not otherwise specified (sPTCL, NOS) and therapy-related myeloid neoplasm (tMN), under an umbrella of myelodysplastic/myeloproliferative neoplasm, namely chronic myelomonocytic leukemia (CMML). Despite aggressive therapeutic management, the patient passed away secondary to disease progression, complications of infection, and multi-organ failure. An appropriate diagnostic approach for complicated cases as described aided in providing the correct diagnosis.

Persistence of Anti-Desmoglein 3 IgG+ B-Cell Clones in Pemphigus Patients over Years

Pemphigus vulgaris (PV) is a prototypic tissue-specific autoantibody-mediated disease in which anti-desmoglein 3 (Dsg3) immunoglobulin G (IgG) autoantibodies cause life-threatening blistering. We characterized the autoimmune B-cell response over 14 patient-years in two patients with active and relapsing disease, then in one of these patients after long-term remission induced by multiple courses of rituximab (anti-CD20 antibody). Characterization of the anti-Dsg3 IgG+ repertoire by antibody phage display (APD) and PCR indicated that 6 clonal lines persisted in patient 1 (PV3) over 5.5 years, with only one new clone detected. Six clonal lines persisted in patient 2 (PV1) for 4 years, of which 5 persisted for another 4.5 years without any new clones detected. However, after long-term clinical and serologic remission, ~11 years after initial characterization, we could no longer detect any anti-Dsg3 clones in PV1 by APD. Similarly, in another PV patient, ~4.5 years after a course of rituximab that induced long-term remission, anti-Dsg3 B-cell clones were undetectable. These data suggest that in PV a given set of non-tolerant B-cell lineages causes autoimmune disease and that new sets do not frequently or continually escape tolerance. Therapy such as rituximab, aimed at eliminating these aberrant sets of lineages, may be effective for disease because new ones are unlikely to develop.

SAT0228 Sustained Clinical Benefit with Multiple Courses of Rituximab in Second Line for ALL Rheumatoid Arthtritis Patients Irrespective to the Inhibitor of Tumour Necrosis Factor Previously Used: 3-Year Data from REPEAT Study

BackgroundIn the last decade, biologic therapy changed dramatically treatment options for rheumatoid arthritis (RA). However, a significant number of patients failed to maintain the initial response to a TNF blocker....

Effects of rituximab on lymphocytes in multiple sclerosis and neuromyelitis optica

ObjectiveTo investigate the effect of rituximab, a B-cell targeted therapy that is used in the treatment of multiple sclerosis (MS) and neuromyelitis optica (NMO), on other immune cells such as CD4+ and CD8+ T-cells in patients with MS and NMO. Design, setting and patientsThis is a retrospective study of all patients with MS or NMO who received at least one rituximab infusion at the UCSF MS tertiary care center between May 2005 and July 2011. Main outcome measuresLinear mixed models were used to assess (a) how post-infusion cell counts changed over time compared to pre-infusion levels and one another; (b) whether the cell counts were different over multiple courses of rituximab; and (c) what was the dosing effect on the cell counts over time. ResultsRituximab initially reduced CD4+ (by 26%, p=0.0005) and CD8+ (by 22%, p=0.0006) T-cells, although these changes were only transient. Subsequent treatments with rituximab did not result in a significant drop in CD4+ or CD8+ T-cells. Changes in other cell types were also typically more marked after the first cycle of rituximab than after additional treatments. The total dose of rituximab received did not appear to have a significant effect. ConclusionsAlthough transient, rituximab-induced decrease in CD4+ and CD8+ T-cells may increase the risk of infection in susceptible individuals.

FRI0240 Correlation between objective and patient self-reported clinical improvement after multiple courses of rituximab in rheumatoid arthritis patients with inadequate response to tumour necrosis factor inhibitors: data from repeat study

BackgroundRituximab (RTX) has been evaluated in many clinical trials and self-reporting instruments have been used in conjunction with objective measurements. Little is known about the relationship between objective and self-reported...

FRI0220 Sustained clinical efficacy after multiple courses of rituximab in rheumatoid arthritis patients with inadequate response to tumour necrosis factor inhibitors: 2-year data from the repeat (repeated courses in routine clinical practice) study

BackgroundIn the last decade, biologic therapy changed dramatically treatment options for rheumatoid arthritis (RA). However, a significant number of patients failed to maintain the initial response to a TNF blocker....

SAT0090 Impact of rheumatoid factor and anti-CCP antibodies on eular response to long-term treatment with rituximab in patients with rheumatoid arthritis after failing one TNFI (first and refirst)

BackgroundReFIRST is an exploratory, multi-center, open label, uncontrolled phase IIIb study evaluating the efficacy of re-treatment with Rituximab (RTX). It is the extension of the FIRST study that included 302...

Incidence of Hypogammaglobulinemia in Patients Receiving Rituximab and the Use of Intravenous Immunoglobulin for Recurrent Infections

Rituximab targets normal B cells and tumor B cells. We used a unique data-mining tool to identify patients with lymphoma who were treated with rituximab and who had serial pre and post rituximab immunoglobulin concentrations evaluated. After treatment, 39% (69/179) of patients had low levels of immunoglobulin G. Recurrent sinopulmonary infections were seen in 6.6% (14/211). Intravenous immune globulin appeared to reduce the frequency of infection. Rituximab has altered the treatment approach to B-cell malignancies and other diseases. Reports consider that rituximab had limited impact on serum immunoglobulins. However, anecdotes suggest that rituximab can cause symptomatic hypogammaglobulinemia. This retrospective study examined the relationship among rituximab, hypogammaglobulinemia, and treatment of symptomatic hypogammaglobulinemia with intravenous immune globulin (IVIG). Patients with serial quantitative serum immunoglobulin (SIgG) concentrations before and subsequent to rituximab administration at Memorial Sloan-Kettering Cancer Center were identified. Information regarding rituximab administration, SIgG concentrations, frequency of infection, and administration of IVIG were recorded. Between December 1998 and April 2009, 211 patients with B-cell lymphoma treated with rituximab and with serial SIgG concentrations were identified. One hundred seventy-nine (85%) patients had normal SIgG before rituximab, 32 (15%) had low SIgG. After rituximab use, hypogammaglobulinemia was identified in 38.54% of patients with initially normal SIgG. The risk was greater in patients who received maintenance rituximab. Symptomatic hypogammaglobulinemia that prompted IVIG administration developed in 6.6% of patients. In this data set, rituximab administration was associated with a high frequency of hypogammaglobulinemia, particularly symptomatic hypogammaglobulinemia, among patients who received multiple courses of rituximab. Baseline and periodic monitoring of SIgGs is appropriate in patients who receive rituximab.

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.

Rituximab therapy for juvenile-onset systemic lupus erythematosus

Rituximab (RTX), an anti-CD20 monoclonal antibody, has been proposed for use in the therapy of systemic lupus erythematosus (SLE). We present the initial long-term experience of the safety and efficacy of rituximab for treatment of SLE in children. Eighteen patients (mean age 14 ± 3 years) with severe SLE were treated with rituximab after demonstrating resistance or toxicity to conventional regimens. There was a predominance of female (16/18) and ethnic African (13/18) patients. All had lupus nephritis [World Health Organization (WHO) classes 3–5] and systemic manifestations of vasculitis. Clinical disease activity of the SLE was scored with the SLE-disease activity index 2K (SLEDAI-2K). Patients were followed-up for an average of 3.0 ± 1.3 years (range 0.5 to 4.8 years). B-cell depletion occurred within 2 weeks in all patients and persisted for up to 1 year in some. Clinical activity scores, double-stranded DNA (dsDNA) antibodies, renal function and proteinuria [urine protein to creatinine ratio (Upr/cr)] improved in 93% of the patients. Five patients required multiple courses of RTX for relapse, with B-cell repopulation. One died of infectious endocarditis related to severe immunosuppression. In conclusion, our data support the efficacy of rituximab as adjunctive treatment for SLE in children. Although rituximab was well tolerated by the majority of patients, randomized controlled trials are required to establish its long-term safety and efficacy.

Rituximab for autoimmune haemophilia: a proposed treatment algorithm

We previously reported durable complete responses following brief courses of rituximab and prednisone with or without cyclophosphamide in four patients with autoimmune haemophilia and inhibitor titres of 5-60 BU. We report here responses to this monoclonal anti-CD20 antibody in four additional patients, including two patients with inhibitor titres >200 BU. Factor VIII levels became normal 2-35weeks after 4 or 8 weekly doses of rituximab, brief courses of prednisone and in one patient immunoglobulin. Complete responses are ongoing at 10 months in two patients. Two patients relapsed: a patient whose initial inhibitor titre was 525 BU relapsed at 3.5 months and a long-term prednisone-dependent patient at 8.5 months. Both responded to second courses of rituximab and prednisone and are in remission. Our experience suggests that rituximab is a safe and effective addition to immunosuppression with prednisone and cyclophosphamide to treat autoimmune haemophilia, and may permit early discontinuation or even avoidance of these potentially toxic agents. High-titre inhibitor patients, however, may require multiple courses of rituximab or the addition of cyclophosphamide. Pending randomized studies, we propose an algorithm based on our experience and other reports for incorporating rituximab in the treatment of this rare disorder.