Rituximab Discontinuation Research Articles

Low risk of hepatitis B virus reactivation in membranous nephropathy patients with resolved infection undergoing rituximab-based regimens without antiviral prophylaxis

IntroductionPatients with resolved hepatitis B virus infection undergoing rituximab are at risk of hepatitis B virus reactivation without antiviral prophylaxis. However, the risk in such patients treated with rituximab-based regimens for membranous nephropathy is not clear. We evaluated the risk of hepatitis B virus reactivation in membranous nephropathy patients with resolved infection undergoing rituximab-based regimens without antiviral prophylaxis. MethodsClinical data of 51 membranous nephropathy patients with resolved hepatitis B virus infection undergoing rituximab-based regimens without antiviral prophylaxis were retrospectively analyzed. Among these, 21 patients were followed for more than 1 year after rituximab discontinuation. The clinical data collected aimed to assess patients’ responses and the risk of hepatitis B virus reactivation during and after rituximab treatment. Results30/51 (58.8 %) patients reached complete or partial remission at 12 months. None of the patients experienced HBsAg seroreversion during rituximab treatment. Alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase and total bilirubin levels, as well as the numbers of patients who exceeded the upper limits of normal for alkaline phosphatase and prothrombin time, did not show any statistically significant difference during rituximab-based therapy. Neither did the anti-HBs level, the number of patients with protective anti-HBs titers exceeding 10 U/L, nor the levels of CD19+ B cells, CD4+ T cells, CD8+ T cells, and natural killer cells. Among the 21 patients followed for 12 (ranging from 12 to 19) months after rituximab discontinuation, no hepatitis B virus reactivation was observed. The mean anti-HBs level and the number of patients with anti-HBs titers over 10 U/L did not show any statistically significant difference during the extended follow-up of 33 patient-years. Neither did the CD4+ T cell, CD8+ T cell, nor the natural killer cell counts. One patient presented with an ALT level that exceeded the baseline value by three times and reached above 100 U/L, accompanied by elevations in AST, GGT, and ALP levels. Meanwhile, the anti-HBs titer was 816.09 U/L, and HBsAg was negative. ConclusionThe administration of rituximab-based regimens in membranous nephropathy patients with hepatitis B virus resolved infection leads to a low risk of hepatitis B virus reactivation without antiviral prophylaxis. Patient’s immune status, drug combination, rituximab strategy should be fully evaluated when considering antiviral prophylaxis therapy.

Relapse during and after regular single-dose rituximab treatment in adult patients with steroid-dependent nephrotic syndrome.

Rituximab is widely used in patients with steroid-dependent nephrotic syndrome. However, information on the effect of long-term rituximab treatment is limited. This study examined the efficacy of rituximab during and after treatment in adult patients with steroid-dependent nephrotic syndrome. This retrospective cohort study included 30 patients with steroid-dependent nephrotic syndrome. Patients received regular single-dose rituximab (500mg) intravenously every 6months. Discontinuation of rituximab was considered after four to six doses if there was no recurrence of nephrotic syndrome. Glucocorticoid discontinuation with remission, first relapse after rituximab initiation, and relapse after regular rituximab treatment discontinuation were evaluated. The median age was 38 (range 18-67) years. Of 30 patients, 13 and 17 were men and women, respectively. Prior to rituximab treatment, the median number of nephrotic syndrome relapses in the patients was 5 (range 2- > 20). The 1year discontinuation rate of glucocorticoids with remission was 83%. All patients discontinued glucocorticoid treatment at least once until 3years and 7months. The 1 and 2year relapse rates after initiation of rituximab treatment were 0% and 3%, respectively. 25 patients discontinued regular rituximab treatment after a median number of six (4-12) doses. Six patients relapsed after discontinuing rituximab, and the 1 and 2year relapse rates after the last regular rituximab treatment were 9% and 25%, respectively. All patients with steroid-dependent nephrotic syndrome who received rituximab could discontinue glucocorticoid treatment with remission, and three-fourths of the patients remained in remission for > 2years after discontinuing rituximab treatment.

Rituximab retention rate in systemic sclerosis: a long term real-life multicenter study.

to report real-life data on rituximab retention-rate as indicator of safety and efficacy in a multicentric national cohort of systemic sclerosis patients. SSc patients treated with rituximab and followed for at least 36 months were included, clinically characterized, and longitudinally monitored. A competing risk analysis with sub-Hazard Ratio(sHR) definition was performed to explore the clinical variables linked to specific cause of rituximab discontinuation. One-hundred-fifty-two SSc-patients (mean age 47.3 ± 12.3 years; females 79.6%; diffuse disease 77.6%; anti-topoisomerase-I positivity 63.2%) were evaluated over a median(IQR) time of 3.3(1.7-5.0) years. The primary indication for rituximab were interstitial lung disease (ILD)(38.8%), worsening skin fibrosis(36.8%), and arthritis(13.8%); 138 patients(90.8%) received more than one rituximab course. The 5-years rituximab retention rate was 59.9%(44.6-64.7%). Clinical response was the most common reason for rituximab discontinuation[5.7(3.7-8.4) per 100 patient-year] and was associated with a shorter disease duration[sHR 0.8(0.7-0.9)], anti-topoisomerase-I negativity[sHR 0.4(0.2-0.9)], previous digital ulcers[sHR 2.6(1.1-6.2] and no history of arthritis[sHR 0.3 (0.1-0.8)]. Treatment failure was the second cause of rituximab discontinuation[3.7(2.2-6.0) per 100 patient-year] and was associated with anti-centromere antibody positivity[sHR 2.8(1.1-7.4)] and anti-topoisomerase-I negativity[sHR 0.2(0.1-0.6)]. Adverse events(AEs) were the less common cause of discontinuation[3.1(1.7-5.2) per 100 patient-year], associated with limited cutaneous subset[sHR 3.4(1.2-9.7)] and previous mycophenolate mofetil treatment[sHR 4.5(1.2-16.3)]. rituximab is a safe and effective treatment in SSc: clinical response emerged as the primary reason for rituximab discontinuation, and AEs had a limited impact on treatment persistence. The identification of specific disease features associated with a response to rituximab will be useful in the management of SSc-patients.

Efficacy and Safety of Golcadomide, a Novel Cereblon E3 Ligase Modulator (CELMoD) Agent, Combined with Rituximab in a Phase 1/2 Open-Label Study of Patients with Relapsed/Refractory Non-Hodgkin Lymphoma

Introduction: Golcadomide is a novel, oral, small-molecule CELMoD ® agent that co-opts cereblon to induce targeted degradation of the transcription factors Ikaros/Aiolos, which are crucial to B-cell malignancy development. We previously reported promising efficacy with a predictable and manageable safety profile of golcadomide in patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (Michot et al. ICML 2023, presentation #90). Methods: CC-99282-NHL-001 (NCT03930953) is a 2-part, multicenter, first-in-human study with dose escalation (Part A) of golcadomide monotherapy and expansion (Part B) ± combination partners. Patients with R/R diffuse large B-cell lymphoma (DLBCL) or R/R follicular lymphoma and disease progression after ≥ 2 lines of therapy or transplant-ineligible patients with R/R DLBCL after ≥ 1 line of therapy were included. Following dose exploration in Part A, golcadomide was administered at 0.2 or 0.4 mg alone or with rituximab on 2 intermittent schedules in Part B. Total duration of treatment is up to 2 years. Here, we report efficacy and safety results for golcadomide + rituximab in patients with DLBCL treated in Part B expansion on a 14 days on/14 days off schedule. The efficacy-evaluable population consisted of patients completing ≥ 1 cycle of golcadomide (taking ≥ 75% of assigned doses) and having baseline and ≥ 1 post-baseline tumor assessment. Results: As of May 10, 2023, 35 patients with DLBCL were enrolled and 34 received ≥ 1 dose of golcadomide or rituximab (safety population); 17 (49%) patients were ongoing and 17 (49%) had discontinued treatment, mostly due to progressive disease (n = 10, 29%). The median age was 60 years (range, 35-80). The median number of prior anticancer therapies was 4.5 (range, 1-11); 68% (n/N = 23/34) of patients had prior CAR T-cell therapy and 49% (n/N = 17/35) were refractory to their last regimen. Golcadomide median treatment duration was 8 weeks (range, 4-48) and median follow up was 15 weeks (range, 2-55). In the efficacy-evaluable population (n = 16), overall response rate (complete response [CR] + partial response) was 50% (n = 8), with CR occurring in 13% (n = 2) of patients. Median duration of response was 17.4 weeks (range, 7.4-45.9). Response data in the 0.2-mg and 0.4-mg golcadomide-treated groups are shown in the table. In the safety population (n = 34), neutropenia was the most common any-grade treatment-emergent adverse event (TEAE), occurring in 15 (44%) patients, all of which were grade 3/4. No febrile neutropenia occurred. The most common treatment-related adverse event (TRAE) for golcadomide was neutropenia (all grade 3/4), occurring in 14 (41%) patients, comprising 5/19 (26%) patients treated at the 0.2-mg and 9/15 (60%) patients treated at the 0.4-mg dose level. Granulocyte colony-stimulating factors were used in 14 (41%) patients. Six serious TRAEs related to golcadomide were reported (n = 1 each), all in the 0.4-mg group. One grade 5 TEAE occurred (tubulo-interstitial nephritis in the 0.2-mg group), which was reported to be due to progressive disease and considered unrelated to study treatment. TEAEs led to golcadomide discontinuation in 2 (6%) patients (1 at each dose level) and rituximab discontinuation in 5 (15%) patients. Similar pharmacokinetic (PK) exposures of golcadomide were observed when golcadomide was dosed alone and in combination with rituximab, indicating no apparent impact of rituximab on golcadomide PK. Analysis of circulating tumor DNA data is underway and will be presented. Conclusions: Golcadomide oral therapy combined with rituximab showed promising efficacy in heavily pretreated patients with R/R DLBCL, including 1 durable response over 300 days. Golcadomide can be safely combined with rituximab, and the combination showed a safety profile similar to that previously reported for golcadomide monotherapy. This study is ongoing, with continued enrolment in the monotherapy and golcadomide + rituximab combination expansion cohorts.

Results from a Phase 1 Study of ACTR707 in Combination with Rituximab in Patients with Relapsed or Refractory CD20+ B Cell Lymphoma

The antibody-coupled T cell receptor (ACTR) platform is an autologous engineered T cell therapy combining the cell-killing ability of T cells and the tumor-targeting ability of coadministered antibodies. Activation of the T cell product ACTR707 is dependent on the engagement of antibody bound to target cells via the CD16 domain of the chimeric receptor (CD16V-CD28-CD3ζ). ACTR707 in combination with the anti-CD20 monoclonal antibody rituximab was evaluated in the ATTCK-20-03 study, a multisite, single-arm, open-label phase I trial in B cell non-Hodgkin lymphoma (NHL). The primary objectives of this study were to evaluate the safety of the combination of ACTR707 and rituximab and to determine a recommended phase 2 dose (RP2D). Secondary objectives included evaluation of antitumor activity and ACTR T cell persistence. The study design included an ACTR707 cell dose escalation phase and an expansion phase at the RP2D. Escalating dose levels of ACTR707 in combination with rituximab were explored in 5 dose cohorts, with 25 subjects receiving study treatment. Subjects received lymphodepleting chemotherapy (cyclophosphamide 400 mg/m2/day and fludarabine 30 mg/m2/day) for 3 days, followed by rituximab 375 mg/m2 and, 24 to 48 hours later, a single dose of ACTR707. Additional doses of rituximab were administered every 3 weeks until disease progression, unacceptable toxicity, or investigator decision. Blood samples were collected at various time points to assess levels of rituximab, cytokines, inflammatory markers, and ACTR707 T cells. The overall response rate of ACTR707 plus rituximab was 56% (14 of 25) across all dose levels. Ten subjects (40.0%) achieved a complete response, with the longest duration of 586 days (range, 85 to 586 days), and 4 subjects (16.0%) experienced a partial response, with the longest duration of 130 days (range, 44 to 130 days). Only 1 case of cytokine release syndrome (grade 2) and no events of neurotoxicity were reported. There were no dose-limiting toxicities or events leading to death. ACTR707 plus rituximab resulted in only 1 adverse event (neutropenia), leading to study discontinuation of rituximab. The ATTCK-20-03 trial serves as proof of principle regarding the ACTR approach that potentially could be used with other antibodies targeting other markers in other malignancies. Although the ACTR707 program has been discontinued, these results may support other programs in the use of similar novel approaches of antibody-coupled T cell activation.

Successful obinutuzumab administration after rituximab discontinuation due to intolerance in patients with hematologic disorders.

Successful obinutuzumab administration after rituximab discontinuation due to intolerance in patients with hematologic disorders.

P1156: MAGNIFY PHASE 3B STUDY OF LENALIDOMIDE + RITUXIMAB (R2) FOLLOWED BY MAINTENANCE IN RELAPSED/REFRACTORY INDOLENT NON-HODGKIN LYMPHOMA: COMPLETE INDUCTION PHASE ANALYSIS

Background: Patients with relapsed indolent NHL (iNHL) have limited standard treatment options. Lenalidomide combined with rituximab (R2) has shown complimentary clinical activity and is a tolerable regimen in both untreated and relapsed or refractory (R/R) patients with iNHL (RELEVANCE: N Engl J Med 2018;379:934 and AUGMENT: J Clin Oncol. 2019;37:1188). Aims: These analyses examine the MAGNIFY interim primary endpoint of overall response rate (ORR; 1999 IWG) for induction R2 in efficacy-evaluable patients receiving ≥ 1 treatment and who have available baseline and post-baseline assessments. Methods: MAGNIFY is a multicenter, phase 3b trial in patients with R/R follicular lymphoma (FL) grades 1–3b, transformed FL (tFL), marginal zone lymphoma (MZL), or mantle cell lymphoma (MCL; NCT01996865) exploring optimal lenalidomide duration. In the induction phase, lenalidomide 20 mg PO on days 1–21 of a 28-day cycle + rituximab IV at 375 mg/m2/week cycle 1 and then every 8 weeks starting with cycle 3 (R2) are administered for 12 cycles. Patients with stable disease, partial response, or complete response/complete response unconfirmed (CR/CRu) were randomized 1:1 to R2 vs rituximab maintenance for 18 months. Data presented here are the complete analysis from the induction phase in efficacy-evaluable patients with FL grades 1–3a or MZL (FL grade 3b, tFL, and MCL not included). Results: As of March 5, 2021, 394 patients (318 [81%] FL gr1–3a; 76 [19%] MZL) were enrolled. The median follow-up was 40.6 mo (range, 0.6–79.6). Median age was 66 y (range, 35–91), 328 (83%) had stage III/IV disease, with a median of 2 prior therapies (94% prior rituximab-containing). ORR was 71% (n = 279) with 42% (n = 164) CR/CRu (Table). All patients have completed R2 induction (n = 232, 59%) or discontinued study treatment (n = 162, 41%). 141 patients (36%) prematurely discontinued both lenalidomide and rituximab, primarily due to adverse events (AEs) (n = 54, 14%) or progressive disease (n = 42, 11%). The majority of patients who have completed induction have been randomized and entered maintenance (n = 217). Median duration of response in the induction period was not reached (95% CI, 43.9 mo–NR), and median progression-free survival in the induction safety population (n = 393) was 50.5 mo (95% CI, 39.5–NR). Efficacy results are reported in the table by histology subgroups (FL vs MZL), and rituximab-refractory, double-refractory, and early relapse statuses. Most common all-grade treatment emergent AEs (TEAEs) were 47% fatigue, 43% neutropenia, 37% diarrhea, 30% nausea, and 30% constipation. Grade 3/4 AEs occurring in ≥ 5% of patients included 37% neutropenia (10 patients [3%] had febrile neutropenia), 8% leukopenia, 6% thrombocytopenia, 5% anemia, and 5% fatigue. TEAEs led to discontinuation of lenalidomide in 19% of patients and rituximab in 12% of patients; reduction or interruption of lenalidomide in 64% of patients; and to interruption of rituximab in 30% of patients (dose reduction for rituximab was not allowed). Neutropenia was the most common TEAE leading to lenalidomide discontinuation in 6% and reduction/interruption in 32%, and rituximab discontinuation in 3%. Infusion-related reaction was the most common TEAE leading to rituximab interruption in 8%. Image:Summary/Conclusion: These data represent complete analysis of all patients in the induction phase of MAGNIFY which continue to support that R2 is active with a tolerable safety profile in patients with R/R FL grade 1–3a and MZL, including rituximab-refractory, double-refractory, and early relapse patients.

Immunogenicity of Rituximab biosimilar GP2013 in chronic inflammatory rheumatic disorders in daily clinical practice

ObjectiveTo study in daily practice the risk of immunogenicity of patients treated with the biosimilar rituximab (RTX) GP2013 used for chronic inflammatory rheumatic disorders. MethodsA prospective monocentric routine care study was carried out between September 2018 and May 2021, including consecutive patients treated with the biosimilar RTX GP2013. Biosamples were taken before each infusion to quantify anti-RTX antibodies (ADAbs) and serum RTX trough levels by ELISA (Lisa Tracker Duo Rituximab, LTR005, Theradiag). Results168 GP2013-treated patients were included (129 who switched from originator RTX and 39 originator RTX naïve). The analysis of 602 samples identified 15 patients (8%) with positive ADAbs including 6 and 9 with transient and persistent ADAbs, respectively. The switch from originator RTX to GP2013 did not increase the risk of immunogenicity, with an incidence rate of 0.8 for 100 patient years. The frequency of persistent ADAs was higher in non-RA patients (5/56, 9% vs. 4/112, 3.5%). Patients with positive persistent ADAbs were more frequently non-caucasian (7/9, 78%, vs. 56/159, 35%, p<0.01) and all had detectable circulating B cells (vs. 40% in ADAb-negative patients, P<0.001). ADAb positivity was not associated with disease activity or RTX discontinuation but patients with ADAb titers >100 ng/mL experienced reduced treatment efficacy or severe infusion-related reaction. ConclusionWithin the study duration, the immunogenicity of GP2013 is a rare event affecting the pharmacodynamics of RTX. Although development of ADAbs had no impact on treatment discontinuation, possible harmful consequences may be observed in patients with high antibody levels.

Rebound of multiple sclerosis in patients treated with anti CD20 after discontinuation of rituximab

In Multiple sclerosis (MS) the “rebound” of disease is a well know phenomenon occurring after the withdrawal of sequestering therapies as Natalizumab or Fingolimod. Until now, we don't know if other treatments acting on B cells as Rituximab or Ocrelizumab, for the specific mechanism of action, could give a reactivation of the disease after the suspension. Here we present a case of MS patient that present a strong reactivation of disease at Rituximab withdrawal.

Long-term safety of rituximab in rheumatic patients with previously resolved hepatitis B virus infection

Conflicting results can be found in the literature on the frequency of hepatitis B virus (HBV) reactivation (HBVr) on rituximab (RTX) in rheumatic patients with previously resolved HBV (prHBV) infection. Here, we report the frequency of HBVr in a large historical cohort of caucasian rheumatic patients with prHBV receiving RTX. Registry data of rheumatic patients treated with RTX were retrospectively analysed. Demographic and clinical characteristics including evaluation of anti-HCV and HBV markers, annual HBV-DNA determination and aminotransferase levels assessed every three months, were recorded. Kaplan-Meier estimate was used to compare the risk of being still under therapy at different time points in patients with or without prHBV infection. Cox regression analysis was used to determine the association between recorded variables and treatment discontinuation. A total of 311 patients treated with RTX, 44 (14.1%) with and 267 (85.9%) without prHBV were analysed. No significant difference between the two groups regarding demographic and clinical characteristics was observed. During RTX treatment, detectable HBV-DNA and reappearance of HBsAg in patients with prHBV (seroreversion) were never observed. Kaplan-Meier functions were similar in patients with or without prHBV infection which was not associated with RTX discontinuation neither at univariate nor at multivariate analysis. These data are in favor of the concept that patients with rheumatologic diseases have a very low risk of reactivation of the HBV infection under RTX treatment. However, future prospective studies, including a larger number of patients, are still necessary to draw definitive conclusions.

Retrospective analysis of safety and outcomes of rituximab for myasthenia gravis in patients ≥65years old.

Optimal management of myasthenia gravis (MG) in individuals ≥65 y old is unknown and patient factors may limit therapeutic choices. Safety and efficacy of rituximab in older patients with MG has not been well-studied. This retrospective study examined 40 patients (14 patients ≥65 y old) treated with rituximab for MG. The primary efficacy outcome was the proportion of patients reaching "Improved" or better on Myasthenia Gravis Foundation of America (MGFA) Post-Intervention Status (PIS) at 12 mo, compared between younger and older patients. Ninety-two percent of patients ≥65 y old achieved MGFA PIS Improved or better at 12 mo compared to 69% of those <65 y old (P=.11). Median prednisone dose for the cohort decreased in the year following rituximab initiation (20 mg [interquartile range, 10-35] to 10mg [0-13], P=.01). Non-refractory MG was predictive of favorable outcome, whereas age was not. Serious adverse events (SAEs) were similar between older and younger patients (21.4% vs. 30.8%, P=.715). No patients ≥65 y old required discontinuation of rituximab due to SAE. One death occurred in a patient <65 y old due to systemic inflammatory response syndrome. At 12 mo following initiation of rituximab for MG, patients ≥65 y old experienced similarly high rates of improvement in their myasthenic symptoms as younger patients, without an increased risk of experiencing SAEs. Rituximab should be considered in the treatment paradigm in older patients and in non-refractory MG patients of any age.

Correlates of Rituximab Discontinuation in Patients with NMOSD: a CIRCLES Cohort Analysis (1489)

Correlates of Rituximab Discontinuation in Patients with NMOSD: a CIRCLES Cohort Analysis (1489)

Long-term persistence of rituximab in patients with rheumatoid arthritis: an evaluation of the UCL cohort from 1998 to 2020.

ObjectivesB cell depletion therapy based on rituximab in patients with RA was pioneered at University College London Hospitals/University College London in 1998. The objective of this study was to evaluate long-term persistence of rituximab and identify factors associated with discontinuation of treatment.MethodsRetrospective review of medical records from all rituximab-treated RA patients followed up in a dedicated clinic (1998–2020). Data collected included gender, disease duration, previous DMARDs, autoantibody status, age and concomitant therapy at first cycle, length of follow-up, and number of cycles. Drug survival and factors associated with drug discontinuation were analysed using Kaplan–Meier survival curves, log-rank test and Cox regression analysis.ResultsA total of 404 patients were included. Median disease duration and age at time of first rituximab cycle were 10 and 57 years, respectively. Median total follow-up was 55 months and median number of cycles five. 93.1% of patients were seropositive. Overall, 31.2% of patients stopped rituximab, with the largest reason for discontinuing being primary inefficacy (42.1%). Comparison of Kaplan–Meier curves showed that rituximab drug survival was lower in seronegative patients and in patients who had previously failed at least one biologic DMARD (bDMARD). Cox regression analysis revealed that rituximab discontinuation was associated with a greater number of previous bDMARDs.ConclusionMany patients with RA achieve good control of their disease with repeated cycles of rituximab treatment. The most common reasons for treatment discontinuation were either primary or secondary inefficacy. Patients who were seronegative and who had previously failed other bDMARDs were more at risk of drug discontinuation.

Efficacy and Safety of Desensitization Therapy in Pediatric Heart Transplant Candidates

<h3>Purpose</h3> Allosensitization to human leukocyte antigen (HLA) in pediatric heart transplant candidates is associated with higher waitlist, post-transplantation mortality and antibody mediated rejection. As limited safety/efficacy data exist on pre-transplant desensitization regimen, we reviewed our institution's experience. <h3>Methods</h3> We reviewed the medical records of 12 highly sensitized (average cPRA = 68%) pediatric heart transplant candidates who underwent desensitization therapy at the University of Virginia Hospital between 2014 and 2020. The following data were collected: individual immunosuppression regimen, pre and post desensitization levels of antibody burden, documented side effects, and incidence of antibody mediated rejection. <h3>Results</h3> The majority of patients received an oral immunosuppressive regimen of Prednisone (0.3 mg/kg/day to max dose of 12.5 mg) and an antimetabolite (Cellcept 60 mg/kg/dose q12 up to 1,000 mg q12 or Imuran 1-2 mg/kg/day) followed by a single infusion of Rituximab (375 mg/m2) and monthly intravenous immunoglobulin (IVIG 2 g/kg) infusions; plasmapheresis was used in one patient and Bortezomib was used in two. cPRA decreased by an average of nearly 20% after an average of 17.5 weeks (Table 1). HLA I antibodies were more susceptible to desensitization than HLA II antibodies (60% vs 36% average antibody reduction, respectively). Immunosuppression medications were well tolerated with only one patient requiring Rituximab discontinuation due to hypotension, tachycardia and respiratory distress. There were no cases of antibody mediated rejection in those patients who underwent transplantation. <h3>Conclusion</h3> In our cohort, B-cell/ antibody targeted therapies were safe and effective in improving allosensitization and allowing for successful transplantation, though HLA II antibodies were more resistant to therapy. Larger scale studies are needed.

Initial Treatment with Lenalidomide Plus Rituximab for Mantle Cell Lymphoma (MCL): 7-Year Analysis from a Multi-Center Phase II Study

Initial Treatment with Lenalidomide Plus Rituximab for Mantle Cell Lymphoma (MCL): 7-Year Analysis from a Multi-Center Phase II Study

THU0175 REAL-WORLD EXPERIENCE OF SWITCHING FROM ORIGINATOR TO BIOSIMILAR RITUXIMAB IN RHEUMATOID ARTHRITIS

Background:Pre-clinical and trial data confirm biosimilar rituximab (RTX-B) has equivalent physicochemical properties, function, efficacy and safety as originator (RTX-O)1,2. However, real-world data are lacking, including non-medical switch to RTX-B in patients established on RTX-O. Loss of response (LOR) has been observed following open-label switch to other biosimilars3, and it is unclear how patients who develop LOR after switching should be managed.Objectives:To describe our real-world experience of non-medical switch from RTX-O to RTX-B in RA and explore treatment strategies for patients developing LOR to RTX-B (switch back to RTX-O versus other b/tsDMARDs).Methods:We conducted a retrospective observational study of RTX-treated RA patients in Leeds from May 2002–Jan 2020. From Oct 2017, all patients on RTX-O were switched to RTX-B unless specified by treating clinician or informed consent not obtained. Demographic and clinical data were collected from electronic health records. Effectiveness was assessed by DAS28-CRP and RTX retention (using Kaplan-Meier method). Changes in treatment were based on clinician judgment.Results:944 patients with RA received ≥1 cycle of RTX in Leeds over the past 17 years. Of these, 358 required RTX re-treatment during the study period (Oct 2017–Jan 2020); 263 (73.5%) switched to RTX-B, whilst 95 (26.5%) remained on RTX-O (medical reason=46.3%; patient decision=53.7%). 256/263 patients on RTX-B with 4-month data were analysed. 201/256 (78.5%) were female, mean (SD) age 63.1 (12.4), 97.7% seropositive, 81.6% on csDMARD (62.9% methotrexate), 14.8% oral steroid, 58.6% had previous bDMARDs, and mean (SD) RTX-O cycles pre-switch was 6 (3.6). Total follow-up was 378 patient-years. Mean (SD) DAS28-CRP was 3.01 (1.17) 4 months post-last cycle RTX-O and 3.32 (1.31) post-switch to RTX-B (mean diff +0.30, 95% CI 0.004-0.60; p=0.047), with increase in VAS (+5.7, 95% CI 0.09-11.37; p=0.047), but not SJC, TJC or CRP. At last follow-up, 185/256 (72.3%) patients remained on RTX-B [median (range) RTX-B cycles 2 (1-4)]. RTX-B retention rate estimates were 79.4% and 71.3% at 12 and 18 months respectively. Following RTX-B discontinuation, 33/256 patients (12.8%) switched back to RTX-O [LOR=30 (11.7%), adverse effects (AEs)=3 (1.2%)], 13/256 (5.1%) started other b/tsDMARDs, and 25/256 (9.7%) stopped treatment (no longer indicated=7, deaths=7, loss to follow-up=6, patient choice=3, new contraindication=2). Of 46 patients with LOR/AE to RTX-B, 39 discontinued after cycle 1 (C1), 5 after C2 and 2 after C3. 31/33 patients switched back to RTX-O remained on treatment but follow-up was limited [mean (SD) 7.5 (5.2) months; 23/33 had 1 cycle only]. Compared with patients treated with other b/tsDMARDs, those switched back to RTX-O had more previous RTX-O cycles [mean (SD) 6.67 (3.28) versus 2.62 (2.10); p&lt;0.0001]. Compared with patients who remained on RTX-B (n=185), those who discontinued for LOR/AE/death (n=53) had more previous bDMARDs (mean 1.26 vs 0.83; difference 0.43, 95% CI 0.10-0.77, p=0.01), but no differences in other clinical characteristics, treatment or B-cell numbers.Conclusion:Our real-world single-centre experience of non-medical switch from RTX-O to RTX-B in RA showed approx. three quarters of patients remained on RTX-B and maintained stable disease activity. However, apparent LOR occurred in 16%. Of &gt;10% switched back to RTX-O, the majority remained on treatment at short-term follow-up.

Alternative anti-CD20 antibody versus desensitization for lymphoma patients with drug hypersensitivity reactions requiring discontinuation of rituximab, obinutuzumab, or ofatumumab.

8062 Background: Immunotherapy with anti CD20 is often associated with mild easily manageable infusion reactions. In rare cases, patients experience severe drug hypersensitivity reactions (DHR) serum sickness or anaphylaxis. These in turn may lead to discontinuation of the drug. In our experience, switching to a different anti-CD20 agent is a feasible alternative to discontinuation or desensitization protocols. Methods: From our pharmacology database we identified all the patients that received rituximab and/or obinutuzumab, and/or ofatumumab, and/or all the patients who received a flat dose of less than 50 mL of the same drugs and were followed at our institution. From the medical record, we identified all the cases where the anti-CD20 antibody was changed due to allergy, serum sickness or other types of DHR, and all those who received minimal doses of anti-CD20 in the context of a desensitization protocol. DHRs were evaluated either by an allergist, or by retrospective review following the World Allergy Organization guidelines. Our primary comparison, was to assess the proportion of pts able to completed planned infusion of abs using either approach (Fisher’s exact Test). Results: Among 343 patients receiving at least two different anti-CD20 antibodies or a flat dose of &lt; 50 mL, we identified 44 patients experiencing severe DHRs needing intervention. At the time of the reaction, 16 (36%) received the anti-CD20 as single agent, 24 (54%) in combination with chemotherapy, 4 (9%) in combination with ibrutinib or lenalidomide. In 9 (20%) patients the reaction was defined as anaphylactoid (8 rituximab; 1 obinutuzumab) and in 8 (18%) patients, all receiving rituximab, as serum sickness. Episodes of DHR were addressed with either desensitization (n = 29) or change of anti-CD20 agent (n = 25), 9 patients received both of these approaches, one patient switched anti-CD20 antibodies twice. Overall, 21 desensitizations were successful (72.4%), 8 failed; 23 changes of anti-CD20 were successful (92%) and 2 failed (p = 0.09). Conclusions: In patients with DHR use of an alternative anti-CD20 antibody is safe and is an alternative or complementary approach to anti-CD20 desensitization.

Physician Experience and Risk of Rituximab Discontinuation in Older Adults With Non-Hodgkin's Lymphoma.

Provider experience, or clinical volume, is associated with improved outcomes in many complex healthcare settings. Despite increased complexity of anticancer therapies, studies evaluating physician-level experience and cancer treatment outcomes are lacking. A population-based study was conducted of older adults (aged ≥66 years) diagnosed with B-cell non-Hodgkin's lymphoma in 2004 through 2011 using SEER-Medicare data. Analysis focused on outcomes in patients receiving rituximab, the first approved monoclonal anticancer immunotherapy. We hypothesized that lower physician experience using rituximab and managing its infusion-related reactions would be associated with early treatment discontinuation. A 12-month look-back from each initiation of rituximab was used to categorize physician volume (0, 1-2, or ≥3 initiations per year). Modified Poisson regression was used to account for provider-level correlation and estimated relative risk (RR) of early rituximab discontinuation (<3 cycles within 180 days of rituximab initiation). Cox proportional hazards were used to measure the impact of rituximab discontinuation on survival. Among 15,110 patients who initiated rituximab with 2,684 physicians, 7.6% experienced early rituximab discontinuation. Approximately one-fourth of patients (26.1%) initiated rituximab with a physician who had no rituximab initiations during the preceding 12 months. Compared with patients treated by physicians who had ≥3 rituximab initiations in the prior year, those treated by physicians without initiations were 57% more likely to experience early discontinuation (adjusted RR [aRR], 1.57; 95% CI, 1.35-1.82; P<.001 for 0 vs ≥3, and aRR, 1.19; 95% CI, 1.03-1.37; P=.02 for 1-2 vs ≥3). Additionally, rituximab discontinuation was associated with higher risk of death (adjusted hazard ratio, 1.39; 95% CI, 1.28-1.52; P<.001). Lower oncologist experience with rituximab was associated with increased risk of early rituximab discontinuation in Medicare beneficiaries with non-Hodgkin's lymphoma. Physician-level volume may be an important factor in providing high-quality cancer care in the modern era.

Predicting Severe Infection and Effects of Hypogammaglobulinemia During Therapy With Rituximab in Rheumatic and Musculoskeletal Diseases.

To evaluate predictors of serious infection events (SIEs) during rituximab (RTX) therapy and effects of hypogammaglobulinemia on SIE rates, and humoral response and its persistence after discontinuation of RTX in the treatment of rheumatic and musculoskeletal diseases (RMDs). A retrospective longitudinal study of 700 RMD patients treated with RTX in a single center was conducted. Immunoglobulin levels were measured at baseline and at 4-6 months after each treatment cycle. Baseline predictors of SIEs were assessed using multivariable logistic regression; for RTX cycles 2-4, a mixed-effects logistic regression model was used. A total of 507 patients (72%) had rheumatoid arthritis, 94 (13%) had systemic lupus erythematosus, 49 (7%) had antineutrophil cytoplasmic antibody-associated vasculitis, and 50 (7%) had other RMDs. The number of SIEs recorded was 281 in 176 patients (9.8 per 100 person-years). Predictors of SIEs included non-RTX-specific comorbidities (previous history of SIE, cancer, chronic lung disease, diabetes mellitus, and heart failure), higher corticosteroid dose, and RTX-specific factors, including low IgG (<6 gm/liter) both at baseline and during treatment, RTX-associated neutropenia, higher IgM, and longer time to RTX re-treatment, but not B cell count or depletion status. Of 110 patients with low IgG, SIE rates were higher in those with low IgG at baseline (16.4 per 100 person-years) and in those who acquired low IgG during or after RTX treatment (21.3 per 100 person-years) versus those with normal IgG (9.7 per 100 person-years). Five of 8 patients (63%) had impaired humoral response to pneumococcus and hemophilus following vaccination challenge, and only 4 of 11 patients (36%) had IgG normalized after switching biologic disease-modifying antirheumatic drugs. Immunoglobulin levels should be monitored at baseline and before each RTX cycle to identify patients at risk of SIEs. Individualized risk-benefit assessment should be undertaken in those with lower IgG as this is a consistent SIE predictor and may increase infection profiles when RTX is switched to different therapies.

Factors influencing the choice of biologic therapy following Rituximab in patients with rheumatoid arthritis: A retrospective study using propensity score.

To assess factors influencing the choice and effectiveness of biological disease-modifying antirheumatic drugs (DMARDs) following failure of rituximab (RTX) in rheumatoid arthritis (RA), taking patient profile into account. In a retrospective, multicenter study, data about RA patients starting a new biologic during the year after RTX discontinuation were collected at baseline (when the biologic was introduced after RTX), and during follow-up (3, 6, and 12 months). Characteristics of patients receiving tocilizumab (TCZ), abatacept (ABA), or a TNFα inhibitor (TNFi), EULAR response, and retention rate were compared using multidimensional factorial analysis for patient profiles and multivariate analysis including propensity score built on the patient profile. Among 152 patients analyzed (37.5% TCZ, 31.6% ABA, 30.9% TNFi), sex, disease characteristics and activity, concomitant DMARDs or glucocorticoids, and previous use of RTX and TNFi were similar at baseline. Patients receiving ABA were slightly older. Multimorbidity index was higher but not significantly different. Multidimensional factorial analysis showed a distinct profile of patients receiving ABA, characterized by older age, more men, more smokers, more comorbidities, and higher anti-cyclic citrullinated peptide antibody. At 1 year, drug retention was higher for ABA than TNFi after adjustment for disease duration, concomitant DMARDs, glucocorticoids, and propensity score (P=0.04). Tolerance and serious infections were similar among groups. The profile of patients receiving ABA following failure of RTX differed from TNFi and TCZ using multidimensional factorial analysis. After adjustment for propensity score, drug retention rate remained higher with ABA than TNFi.