Biosimilar Rituximab Research Articles

Catastrophic antiphospholipid syndrome presented with coronary thrombosis, renal impairment, and suspected diffuse alveolar hemorrhage treated with rituximab biosimilar (CT-P10)

Catastrophic antiphospholipid syndrome (CAPS) is a lethal disease that occurs suddenly and progresses to multi-organ failure. We present a case of CAPS successfully treated with the rituximab biosimilar CT-P10. A 38-year-old man was referred with a sustained fever and unexplained elevated creatinine levels. Cardiac arrest by ventricular fibrillation occurred upon arrival at the hospital. We diagnosed probable CAPS because of coronary thrombus, renal impairment, suspected diffuse alveolar hemorrhage, and positive anticardiolipin antibody immunoglobulin G. We performed percutaneous coronary intervention for the cardiac arrest, and treated him with extracorporeal membrane oxygenation, mechanical ventilation, and continuous renal replacement therapy. When CAPS was diagnosed, we administered CT-P10 after administering high-dose glucocorticoid. Our case suggests that the use of a rituximab biosimilar is economically efficient in the treatment of CAPS, as in other rheumatic diseases. The patient was cured without recurrence at the 2-year follow-up.

Comparison of treatment retention of originator vs biosimilar products in clinical rheumatology practice in Sweden.

ObjectivesTo compare treatment retention between biosimilars and their originator products among first starters (etanercept, infliximab, adalimumab and rituximab), as well as after non-medical switch.MethodsPatients with rheumatic diseases starting, for the first time, an originator or biosimilar etanercept, infliximab, adalimumab or rituximab were identified in the national Swedish Rheumatology Quality Register. Moreover, patients switching from an originator to its biosimilar were identified and individually matched to patients continuing on the originator. One-year treatment retention was calculated and hazard ratios (HR) for discontinuation with 95% CIs were estimated, adjusting for comorbidities and socio-economic factors.ResultsIn total, 21 443 first treatment courses were identified. The proportion of patients still on the drug at 1 year and the HR for discontinuation revealed no differences across adalimumab (Humira, Imraldi, Amgevita and Hyrimoz) nor across rituximab products (Mabthera, Ritemvia/Truxima and Rixathon). The proportions on the drug at 1 year were similar for Benepali (77%) and Enbrel (75%) and the adjusted HR for Benepali compared with Enbrel was 0.91 (95% CI 0.83, 0.99). For infliximab, the proportion still on the drug at 1 year was 67% for Remicade and 66% for Remsima/Inflectra and the HR compared with Remicade was 1.16 (95% CI 1.02, 1.33). Among 2925 patients switching from an originator drug to one of its biosimilars, we noted no statistically significant or clinically relevant differences in drug survival compared with those who remained on originator therapy.ConclusionThis large observational study supports the equivalence of biologic DMARD biosimilar products and originators when used in routine rheumatology care.

What does endemic COVID-19 mean for the future of rituximab?

What does endemic COVID-19 mean for the future of rituximab?

Rituximab Biosimilar Combined with Pegylated Interferon α-2b in Patients with Untreated Advanced Indolent B-Cell Non-Hodgkin's Lymphoma: Preliminary Results from a Multicenter, Single-Arm, Phase II Study

Background: Indolent B-cell lymphoma (iBCL) are clinically heterogeneous and accounts for 10-15% of all kind of subtypes in NHL in China. Although iBCL have a relatively good survival, majority of these lymphomas is considered incurable. The favorable activity and safety profile of rituximab monotherapy in the initial treatment of iBCL has been proven. Interferon alpha (IFN-α) has been proven to be effective in modulating immune responses and may enhance the clinical responses to rituximab in vitro and in vivo studies. Clinical combination of rituximab and IFN-α was associated with fewer early treatment failures compared to single agent rituximab. Peginterferon-α-2(peg-IFN-α2) has a longer half-life with less toxicity. It also is one of the options for the treatment of chronic hepatitis B virus (CHB) infection. Therefore, we hypothesized that peg-IFN-α2 may synergize with rituximab and would minimize or eliminate minimal residual disease (MRD). The purpose of this study is to evaluate the efficacy and safety for this combination in pts(pts) with treatment-naive iBCL.Methods: This trial enrolled eligible pts aged 18-80 years with newly diagnosed iBCL including FL(grade 1-2,3a) and MZL. Pts were eligible if they had ECOG ≤ 2, adequate organ function and bone marrow function, and at least one measurable or evaluable lesion. Further eligibility criteria were HBsAg positivity with HBV DNA load <3000 IU/mL prior to study; serum ALT level of <5 times the upper limit of normal. During induction phase, pts received rituximab biosimilar (Henliritux ® Shanghai Henlius Biotech) 375 mg/m 2 intravenous infusion on d1. Peg-IFN-α2b (Pegberon ®, Xiamen Amoytop Biotech) was given at a dose of 135ug, subcutaneously, on d1,8. The combination repeated every 21 days for 6 cycles. Responded pts receive rituximab (every 2 months) plus peg-IFN-α2b (every month) maintenance at the dose described above, for up to 2 years until disease progression and intolerance. Simultaneously, CHB pts orally treated with entecavir continuously. The primary endpoint is ORR assessed by investigators per Lugano 2014 criteria. Key secondary endpoints included TTR, DOR, PFS, OS, HBV DNA load clearance, and safety. Adverse events (AEs) were summarized according to NCI CTCAE v5.0. All pts' blood samples were collected for circulating tumor DNA (ctDNA) assessment before treatment in each of cycles. ctDNA samples were analyzed by capture-based NGS targeting 475 lymphoma- and cancer- relevant genes. This trial was registered at ClinicalTrials.gov (NCT04246359).Results: From January 2020 to July 2021, 52 eligible pts with median age of 54 (range, 29-75) years were enrolled from 6 institutions in China. Thirty (54.5%) are female, 20(36.4%) pts were symptomatic and 22(40.7%) pts with FLIPI score≥3, 6(10.9%) pts suffer from hepatitis B with HBV DNA load <3000 IU/mL at study entry. At cutoff date, there were 25(46.3%) FL (grade 1-2), 19(35.2%) MALT, 8(14.8%) FL (grade 3a) pts enrolled. Of 50 response evaluable pts, 31(62.0%) pts achieved an objective response including 19(38.0%) pts with CR based on investigators. ORR were 58.3% (14/24), 75.0% (6/8), 61.1% (11/18) and the CR rates were 29.2% (7/24), 62.5% (5/8), 38.9% (7/18), 0,0 for FL (grade 1-2), FL (grade3a), MALT respectively. Median HBV DNA load clearance time was 1.8 months (1.3-2.1months), no hepatitis B virus reactivation reported. With median follow-up time was 6.2 months (range: 1.4-18.3 months), median OS, PFS and DoR was not reached; 6-month OS and PFS rate of whole cohort was 96.7±3.3%, 85.3±6.1%, respectively. Median TTR was 3.0months (1.5-5.2months). Dynamics ctDNA assay is in progress, data in detail will be reported at the ASH conference. The most common treatment-emergent adverse events (TEAEs) were hematological relevance toxicities. The most common grade hematological TEAEs (>30%) were neutropenia 63.5%, anemia 34.6%, thrombocytopenia 28.8%. Non-hematological TEAEs (>10%) were fever (28.8%), transaminase elevated (28.8%), fatigue (26.9%), infusion reaction (17.4%). Most common grade 3-4 TEAEs (>5%) were neutropenia（17.3%）, anemia (7.7%). No treatment-related death occurred.Conclusion: Rituximab biosimilar plus pegylated interferon α-2b provided favorable response in newly diagnosed advanced iBCL and was well tolerated. No hepatitis B virus reactivation was observed. Further investigation is warranted. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Follicular Lymphoma Microenvironment Signatures Define Patients Subsets Obtaining Long Term Clinical Benefit after Single-Agent First-Line Anti-CD20 Immunotherapy

The role of first-line single agent Rituximab immunotherapy in follicular lymphoma (FL) is still a matter of debate. Although a subset of patients (pts) may obtain long term benefit with upfront immunotherapy, first-line therapy with standard chemoimmunotherapy offers better results in terms of progression free survival (PFS) compared to single agent Rituximab. On the other hand, there is no clear demonstration of sizeable long term benefit with first-line Rituximab compared to an initial wait and see approach, as most FL pts will ultimately be exposed to chemotherapy at some point in their disease course.Here we show that the efficacy of front line anti CD20 immunotherapy in FL could be dependent on microenvironmental factors, and that specific immune signatures could define FL pts subsets obtaining maximal benefit from upfront anti CD20 immunotherapy.First, we retrospectively analyzed the outcome of our single center cohort of 81 FL pts treated with first-line single agent Rituximab therapy with (n=53) or without (n=28) maintenance. The vast majority of pts considered in this analysis were treated in the context of several clinical trials exploring the efficacy of upfront single agent originator (SAKK 35/98, 35/03, 35/10: n= 68) or biosimilar (JASMINE and REFLECTIONS B328/06 n= 9) Rituximab, which were ran at our center from 2000 to 2018. Four patients received off-label single agent Rituximab. Median age was 55 years (y), 52% (42) of patients were female, 72% (58) stage III-IV, 76% (62) were Follicular international prognostic index (FLIPI) score 0-2, 26% (21) were bulky, 52% (42) were high tumor burden according to the GELF criteria. After a median follow-up of 9.5 y, the overall survival (OS) and PFS rates were 82% and 35% respectively. With a long follow-up, these data are in line with previous findings indicating that a sizeable fraction of FL pts derive long term benefit from upfront single agent Rituximab maintaining a continuous complete remission. Paraffin embedded tissue from initial diagnosis was available in 39 pts. In order to dissect determinants of Rituximab immunotherapy efficacy in this homogeneous chemo-naive population, we analyzed FL diagnostic biopsies (n=39 FL + 5 healthy controls) with targeted gene expression profiling (T-GEP) on the NanoString platform, using the PanCancer Immune Profiling panel, which includes 730 genes belonging to the most relevant immunologic checkpoints and pathways.A 20-gene signature including genes involved in chemokine-cytokine signaling, T-regulatory cells, natural-killer cell activity and interleukin-17 signaling was significantly associated with the achievement of a complete response after induction +/- maintenance treatment. A simple 6-gene immune signature (hereafter ImSig) was found to be significantly associated with PFS, with IL22RA2, CCL22, TNFRSF4, IL17RB, CCL19 overexpression and CD209 downregulation being associated with worse outcome. By applying the maxstat package 10-y PFS was 65% for ImSig low pts vs 6% for ImSig high pts (p<0.0001). In multivariate analysis only the 6-gene ImSig and Rituximab maintenance retained independent prognostic value (p<0.001 and 0.002 respectively). As opposite, GELF criteria (present/absent = 27/12) and FLIPI score (0-2/3-5 = 23/16) were not associated with PFS. The 6-gene immune signature was validated in silico in 2 independent publicly available cohorts of FL pts treated with upfront chemoimmunotherapy: a cohort of 137 pts (Silva et al 2019, Affimetryx platform) and a cohort of 50 pts (Bararia et al. 2020), the latter analyzed on the NanoString Platform with the same T-GEP panel (PanCancer Immune Profiling) used in our discovery cohort. The 6-gene signature was confirmed to be a powerful outcome predictor in these 2 chemoimmunotherapy-treated cohorts, and notably the 10-y PFS rates of ImSig low vs high patients mirrored the results observed with single agent immunotherapy in the discovery cohort.The results here reported indicate that pts with a favorable immune signature could derive maximal benefit from a first-line chemo-free treatment approach with single agent Rituximab, achieving and maintaining complete remission in the long term, irrespective of the tumor burden and other clinical variables. Thus, profiling of FL microenvironment with T-GEP could provide a useful tool for selecting patients who may be suitable for a chemo-free upfront treatment with anti CD20 immunotherapy. DisclosuresDerenzini: TG-THERAPEUTICS: Research Funding; ASTRA-ZENECA: Consultancy, Other: ADVISORY-BOARD; ADC-THERAPEUTICS: Research Funding; TAKEDA: Research Funding; BEIGENE: Other: ADVISORY BOARD. Pileri: CELGENE: Other: ADVISORY BOARD; NANOSTRING: Other: ADVISORY BOARD; ROCHE: Other: ADVISORY-BOARD. Tarella: ADC-THERAPEUTICS: Other: ADVISORY BOARD; Abbvie: Other: ADVISORY BOARD. OffLabel Disclosure:First line single agent Rituximab in Follicular Lymphoma

R-CHOP Chemotherapy Including Biosimilar Rituximab (Redditux ®) for De-Novo Diffuse Large B-Cell Lymphoma Patients: Real-Life Single Center Experience

BackgroundThe biosimilar rituximab (Redditux) was approved in Turkey for all indications of the reference molecule (MabThera) in March 2018. Large clinical trials and real-life experiences are lacking in hematological malignancies.AimsWe aimed to evaluate the efficacy and safety of Redditux in de-novo diffuse large B-cell lymphoma (DLBCL).MethodsOur institution decided to provide Redditux for hematological indications since February 2019. We retrospectively analyzed medical records of 51 consecutive de-novo DLBCL patients (pts) diagnosed between February 2019 and September 2019 in the hematology department of Istanbul University Istanbul Medical Faculty. We compared the response rates with historical controls treated with MabThera-CHOP at Cerrahpaşa Medical Faculty. Our study was approved by I.U. Istanbul Medical Faculty Ethical Committee (2019/1454).ResultsA total of 51 pts without CNS involvement received Redditux-CHOP. Median follow-up was 24 months (range: 8-31). A median of 6 cycles of biosimilar (range: 4-8) was administered. Four pts with high CNS-IPI score received four intrathecal methotrexate injections and 13 pts had additional radiotherapy for their initial bulky disease. The patient characteristics and response rates of the Redditux and historical MabThera cohorts are summarized in Table 1.Apart from 6 cases who were refractory to Redditux-CHOP, 8 pts had progressive disease (6 with CR, 1 with PR and 1with SD) in the follow-up. The median time to relapse was 11.5 months for 6 cases who had CR following first-line treatment. Five of 8 cases with PD experienced CNS relapse. Their CNS-IPI score (Schmitz et al. J Clin Oncol 2016) were low in 2 pts, intermediate in 2 pts and high in 1 patient. Of 11 pts with bone involvement at the time of diagnosis, three cases had CNS relapse (p=0.028). Two pts with CNS relapse were treated with intrathecal chemotherapy only due to their poor performance status. Eight pts received salvage combination chemotherapy [R-ICE (n=3); R-benda (n=3); R-DHAP (n=1); MATRix (n=1)] and two of them responded. One of these 2 cases underwent auto-SCT and the other proceeded to allo-SCT; however, he died during conditioning treatment.Ten pts died in the follow-up. Causes of death were progressive disease (n=7, two cases with CNS involvement), infection during allo-conditioning (n=1), post-COVID herpes zoster infection (n=1) and unknown (n=1).The 24 month PFS and OS rates were 75.8% (95% CI: 0.61-0.85) and 80.3% (95% CI: 0.67-0.89) for Redditux cohort, respectively. In the historical MabThera group, the 24 month PFS and OS rates were 85.2 (95% CI: 0.79-0.90) and 81.4% (95% CI: 0.75-0.86), respectively.For pts with high R-IPI score in the Redditux cohort (3-5); the 24-month PFS and OS rates were 54.2% (95% CI: 0.29-0.74) and 55.6% (95% CI: 0.31-0.75), respectively. In the historical Mabthera group, the 24-month PFS and OS rates were 68.7% (95% CI: 0.53-0.80) and 59.4% (95% CI: 0.47-0.70), respectively. Although the PFS rates seems to be worse in high R-IPI cases receiving Redditux, the difference was not significant (p=0.18; Figure 1).AEs were reported in 51% (n=26) of patients. Most common AE was grade 2 infusion reactions (shivering, nausea, fever) requiring medical intervention in 20% of pts, accompanied with rash in half of them. Grade 3&4 AEs were leucopenia (n=2; 4%), neutropenia (n=20; 39%) febrile in 2 cases, anemia (n=6; 12%), thrombocytopenia (n=3; 6%). Grade 2 pneumonia (n=2) and urinary tract infections (n=2) were other infectious complications.ConclusionAlthough the PFS rate at 24 months in high-IPI group treated with Redditux seems to be lower compared to MabThera treated historical control group, survival rates were not significantly different. Our results should be cautiously evaluated due to small sample size. Compared to the original trial of MabThera added to CHOP based regimen, (Coiffier et al N Eng J Med. 2002), our CR rates in stage 2-4 pts seem to be slightly lower (70.7% vs 76%), although the OS rates are quite similar (86.3% vs 82%). Grade 3&4 neutropenia requiring empirical administration of G-CSF was 39% in our cohort. Infusion reactions were observed in 20% of pts, which was reported to be around 30% with original molecule (Patel et al. Clin Lymphoma Myeloma Leuk 2019). The CNS relapse rate was relatively high (9.8%) in our cohort. Prospective randomized clinical trials are needed to determine the efficacy and safety profile of Redditux. [Display omitted] DisclosuresFerhanoglu: Takeda Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees.

Cyclodextrins as modulators for separation of charged variants of mAbs by capillary zone electrophoresis

Charge heterogeneity is a critical quality attribute for mAb-based therapeutics. Its characterization involves the identification of charge variant species in the final formulation. Capillary zone electrophoresis (CZE) is a valuable tool to assess charge heterogeneity, but typically offers incomplete separation of the different charged isoforms. Cyclodextrin-mediated chiral CE is a well-established electromigration method. In this paper, we propose the use of cyclodextrins as modulators for CZE based separation of mAb charge variants. Uncoated fused silica capillaries have been used for examining charge heterogeneity in biosimilars of Rituximab and Trastuzumab in presence of different cyclodextrins. Both the negatively charged CMβCD and uncharged HPβCD have been explored. The effect of cyclodextrin concentration has been found to impact the extent of modulation of resolution of charge variants. Addition of 10 mM CMβCD not only improved resolution but also resulted in separation of two additional basic and one additional acidic species for Rituximab. Similarly, besides improvement in the resolution of separation, one additional basic variant was observed with 2.5 mM CMβCD with another sample, Trastuzumab. The paper demonstrates that the effect of CMβCD is mAb specific. No improvement in resolution was, however, observed with HPβCD, suggesting the selective nature of cyclodextrins for mAb variants.

Expression of interferon-stimulated genes in patients with rheumatoid arthritis on anti-B-cell therapy (preliminary results)

Objective: to evaluate the expression of interferon-stimulated genes (ISG) – interferon (IFN) signature – in patients with rheumatoid arthritis (RA) and its dynamics during anti-B-cell therapy.Patients and methods.We examined 20 patients with RA who received two infusions of the biosimilar rituximab (RTM) Acellbia® in a total dose of 1200 mg. Five genes were selected to evaluate IFN signature: IFI44L, MX1, IFIT1, RSAD2, EPSTI1. The expression of IFI44L and IFIT1 could not be determined for technical reasons, and further analysis included three genes – MX1, EPSTI1, RSAD2. IFN signature was calculated as the average value of the expression of three selected genes (IFN-score).Results and discussion. The initial expression level of MX1 was 11.48 (5.45–19.38), EPSTI1 – 12.83 (5.62–19.64), RSAD2 – 5.16 (2.73–10.4) and IFN-score –10.3 (5.18–17.12), in patients with RA it was statistically significantly higher than in healthy donors: 1.26 (0.73–1.6); 1.06 (0.81–1.48); 0.93 (0.72–1.19) and 1.09 (0.92–1.42), respectively (p&lt;0.05). The IFN-score was high in 15 (75%) patients, low in 5 (15%). The use of RTM was accompanied by a statistically significant decrease in disease activity and the level of acute phase parameters (ESR, CRP) after 12 and 24 weeks of therapy (p&lt;0.05). In the group as a whole, as well as in patients with a moderate effect of therapy or its absence, by the 24th week of treatment, an increase in the expression of RSAD2 (p&lt;0.05) and a tendency to an increase in the IFN-score level (p=0.06) were observed.Conclusion. In patients with RA, an increased expression of ISH was found compared to healthy donors. An increase in the expression of RSAD2 and IFN-score is observed both in patients with a satisfactory effect of RTM and with no effect. The obtained results can be important for predicting the course of the disease and personalizing therapy.

RITUXIMAB BIOSIMILAR RTXM83 POST-MARKETING SURVEILLANCE IN BRAZIL: EVALUATION OF THE ADVERSE EVENTS SPONTANEOUSLY REPORTED TO PHARMACOVIGILANCE

Biosimilars are highly similar to their reference products, but unlike generic drugs, they are not identical. Differences between a biosimilar and its reference product may arise because of the complexity of biologics, differences in the cell lines and processes used during manufacturing. Biosimilars are approved in Europe, United States and Brazil through a regulatory pathway based on comparative analytical, clinical studies and demonstration of no clinically meaningful differences from their reference products. Post marketing pharmacovigilance is a useful tool to confirm the safety profile of biosimilar medication in the general population, outside of controlled environment of clinical studies. In 2019, rituximab biosimilar RTXM83 was approved in Brazil. The purpose of this communication is to present rituximab biosimilar RTXM83 information collected from adverse events (AEs) spontaneous reports during post-marketing pharmacovigilance activities in Brazil. Descriptive retrospective study. Treatment related data and AEs from all spontaneous reports with biosimilar rituximab RTXM83 were reviewed. AEs were classified according to medical terminology (MedDRA) and seriousness assessed by the CTCAE (Common Toxicity Criteria) version 5.0 scale. Descriptive analysis of demographic data and AEs reported was performed. A total of 32 reports containing 59 adverse events (AEs) were received from spontaneous reports between September 2019 and July 2021. From 32 reports, 19 were female, 12 were male and 1 not informed. The patients mean age was 48,8 (13 to 81years). The treatment indication was hematology oncology diseases in 23 (72%) patients, autoimmune disease in 7 patients (22%) and not informed in 2 (6%) patients. Regarding AEs seriousness and expectedness, 26 (44%) were non-serious AEs (24 expected / 2 unexpected) and 33 (56%) were serious AEs (22 expected / 11 unexpected). The five most frequently reported AEs according to SOC (System Organ Classification) were immune system disorders 19 (32%), blood and lymphatic system disorders 14 (24%), nervous system disorders 4 (7%), investigations 3 (5%), respiratory, thoracic and mediastinal disorders 3 (5%). The five most commonly reported adverse events (MedDRA PT - Preferred term) were infusion related reaction 18 (31%), neutropenia 6 (10%), anaemia 3 (5%), leukopenia 2 (3%), thrombocytopenia 2 (3%). AEs spontaneously reported in patients treated with biosimilar rituximab RTXM83 were consistent with the reference safety information based on literature data and the Summary of Product Characteristics (SmPC) of the reference product. No new safety signals were detected.

Dynamics of the level of calprotectin in patients with rheumatoid arthritis during rituximab biosimilar (Acellbia “Biocad”) therapy

Objective.To study the relationship between the level of calprotectin (CP) and RA activity, the level of acute phase reactants, proinflammatory cytokines, chemokines and growth factors, to assess its dynamics during rituximab (RTM) biosimilar therapy.Material and methods.20 patients with RA were examined. All patients received 2 intravenous infusions of RTM (Acellbia®) at a dose of 600 mg with an interval of 2 weeks against the background of methotrexate therapy. The level of CP in blood serum was measured by ELISA.Results.Before starting DAS28 (5.6 [4.9–6.8]), SDAI (27.17 [23.08–39.9]) and CDAI (26.6 [22.25–37.0]) corresponded to the high disease activity. A decrease in disease activity was noted after 12 and 24 weeks of therapy: the DAS28 value was 4.28 [3.24–4.75] and 4.14 [3.11–4.66], respectively (p&lt;0.05). Before the start of therapy, patients with RA had a higher CP level compared with healthy donors 9.68 (4.5–21.5) and 2.39 (1.52–4.45) μg/ml, respectively (p&lt;0.05). Against the background of RTM therapy, there was a decrease in the CP level 12 weeks after the first infusion of the drug in the group as a whole by 26.5% from the initial level, among patients with moderate/no effect of therapy – by 32.7% from the initial level.Conclusion.The CP level significantly decreases during therapy and can be used to monitor the effectiveness of therapy. The predictive value of this laboratory parameter requires further study.

R-CHOP Chemotherapy with a Rituximab Biosimilar (Redditux&lt;sup&gt;®&lt;/sup&gt;) for Patients with &lt;i&gt;de novo&lt;/i&gt; Diffuse Large B-cell Lymphoma: First Preliminary Results of a Real-Life Single-Center Experience from Turkey

R-CHOP Chemotherapy with a Rituximab Biosimilar (Redditux&lt;sup&gt;®&lt;/sup&gt;) for Patients with &lt;i&gt;de novo&lt;/i&gt; Diffuse Large B-cell Lymphoma: First Preliminary Results of a Real-Life Single-Center Experience from Turkey

Impact of rituximab biosimilars on overall survival in diffuse large B-cell lymphoma: a Dutch population-based study

AbstractIn 2017, the European Medicines Agency approved rituximab biosimilars (R-biosimilars) for treatment of diffuse large B-cell lymphoma (DLBCL). Thereafter, the Netherlands was one of the first countries to implement R-biosimilars, given lower costs compared with rituximab originator (R-originator). This study's objective was to investigate whether overall survival (OS) of patients with DLBCL receiving R-biosimilars is similar to patients treated with R-originator. DLBCL patients ≥18 years, diagnosed between 2014 and 2018, who received at least 1 cycle of rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) were identified in the Netherlands Cancer Registry. Patients were categorized into R-originator or R-biosimilars groups based on data from a central repository of the Dutch medicinal drug market. The primary end point was 3-year OS, defined as the time between diagnosis and all-cause death. By the end of 2018, 91% of purchased rituximab were biosimilars. In total, 4429 patients were identified with 876 in the R-biosimilars group and 3553 in the R-originator group. Patients in the R-biosimilars group less frequently received >6 cycles of R-CHOP compared with patients treated with R-originator (24% vs 30%, P = .003). The 3-year OS did not differ between patients treated with R-originator or R-biosimilars (73% vs 73%, P = .855). This was confirmed with a multivariable Cox regression analysis accounting for sex, age, International Prognostic Index score, and number of R-CHOP cycles. In conclusion, the 3-year OS is similar for patients treated with CHOP in combination with R-originator or R-biosimilars and, therefore, favors the use of R-biosimilars in DLBCL treatment management.

Rituximab biosimilars for B-cell lymphomas: a decade of real-world experience from India

The survival of patients with B-cell non-Hodgkin lymphomas increased after the introduction of the anti-CD20 monoclonal antibody, rituximab to the market; however, it remained unaffordable and underused in low-income and middle-income countries for over a decade. In 2010, our group, then at the Tata Memorial Center, Mumbai, India, found that only 35% of our patients with diffuse large B-cell lymphoma were able to afford rituximab, resulting in a 20% reduction in 2-year overall survival compared with those who took rituximab.

Real-world use and acceptance of biosimilar monoclonal antibodiesof rituximab in oncology practice in the USA.

Aim: To describe treatment patterns and patient and provider characteristics associated with the recently introduced biosimilarrituximab-pvvr. Methods: This retrospective analysis included adult patients with one or more claims for rituximab-pvvr, withan index date of 23January 2020and astudy period covering 1January2019-31July2020. Results: Of 249 patients included, the most common rituximab-pvvr indications were non-Hodgkin's lymphoma (77.5%) and chronic lymphocytic leukemia (11.2%). Some patients withnon-Hodgkin's lymphoma (42.5%) and chronic lymphocytic leukemia(39.3%) switched to rituximab-pvvr from the reference product or another rituximab biosimilar. Most patients were aged ≥65years (63.5%) and weremale (54.6%). Most (59.0%) rituximab-pvvr prescribers practiced in the south of the USA. Conclusion: Utilization occurred in approved and extrapolated indications. These preliminary findings suggest switching between reference product and rituximab biosimilars;rituximab-pvvr combination regimensare being adopted in real-world oncology practice.

Clinical Factors Impact on Pharmacokinetics of CT-P10 and Reference Rituximab in Patients with Advanced-Stage Follicular Lymphoma

Background: CT-P10 is the first biosimilar to the innovator rituximab (RTX), which was approved by the European Medicines Agency for all indications for which RTX is approved. Pharmacokinetic equivalence and comparable efficacy was demonstrated in advanced-stage follicular lymphoma patients (Kim WS et al. Lancet Haematol. 2017; S2352-3026(17)) as well as in rheumatoid arthritis (Yoo DH, et al. Arthritis Rheumatol. 2016; 68 (suppl 10)). It is known that there are several factors affecting on pharmacokinetics (PK) of rituximab. However, there are limited data on comparing PK data between a biosimilar of rituximab and RTX with different subgroups in advanced-stage follicular lymphoma (AFL) patients.Objective: This report is to investigate the PK of CT-P10 according to the several relevant clinical factors and to compare with RTX in the post-hoc analysis of randomized controlled trial to compare CT-P10 and RTX in advanced-stage follicular lymphoma (NCT02162771).Methods: A total of 121 patients of PK population were included in this analysis. Fifty nine patients in the CT-P10 group and 62 patients in the RTX group received CT-P10 or RTX (375 mg/m2 i.v) plus CVP (cyclophosphamide, vincristine and prednisone) for every 3 weeks over 8 cycles. Area Under the Concentration-time curve at steady state (AUCtau) and the maximum serum concentration at steady state (CmaxSS) at Cycle 4 and trough serum concentration (Ctrough) at Cycle 4 and Cycle 8 were calculated by standard non-compartmental methods using Phoenix WinNonlin. The parameters were analysed by subgroups of Gender (male vs. female), Eastern Cooperative Oncology Group (ECOG) Performance Status (0 vs. ≥1), Follicular Lymphoma International Prognostic Index (FLIPI) Score (0-2 vs. 3-5) and its component (Age (≥60 vs. <60), Hemoglobin [Hb] (≥120g/L vs. <120g/L), Lactate dehydrogenase [LDH] (>UNL vs. ≤UNL), number of nodal sites (>4 vs. ≤4)), presence of bulky lesion at baseline (≥7cm vs. <7cm) and Complete response (CR)/Complete response unconfirmed (CRu) as best overall response assessed by International Working Group 1999 in the each and combined group of CT-P10 and RTX. Outliers which determined by robust regression outlier testing were excluded in this analysis. For AUCtau, 7 patients (5 in the CT-P10 group and 2 in the RTX group) and among them, 4 patients (2 patients in each group) for CmaxSS were defined as outliers.Result: Higher AUCtau and CmaxSS were observed in patients who are female, under 60 years old, good ECOG Performance Status, low FLIPI score, normal Hb and LDH levels, and non-bulky disease at baseline as shown in Table 1. In patients who achieved CR/CRu as their best overall response during 8 cycles showed higher AUCtau, CmaxSS and Ctrough than in patients who did not achieve CR/CRu response in both CT-P10 and RTX groups. At Cycle 4 and Cycle 8, mean Ctrough in the CR/CRu responder were 72 μg/mL, 108 μg/mL, respectively, and those concentrations are 56 μg/mL, 96 μg/mL in the CR/CRu non-responder. Importantly, there was no statistically significant difference between the CT-P10 and RTX in any of subgroup analyses; confidence interval of the ratio of geometric mean of CT-P10 to RTX contains 1 using Satterthwaite approximation for each comparison.Conclusion: Female gender, younger age (<60), better ECOG Performance Status, lower FLIPI score, LDH and Hb levels in normal range, absence of bulky disease at baseline and better response are factors associated with increased serum rituximab concentration in the combined treatment groups. No statistically significant differences were found between CT-P10 and RTX groups in PK at all subgroup analyses. Therefore, this result shows that the PK of CT-P10 is in accordance with the RTX from historical data and further supports the PK similarity between CT-P10 and RTX. [Display omitted] DisclosuresKim:Celltrion, Inc: Consultancy, Honoraria; Roche: Research Funding; Mundipharma: Research Funding; Novartis: Research Funding; Kyowa-Kirin: Research Funding; Donga: Research Funding; J&J: Research Funding; Takeda: Research Funding. Coiffier:Celltrion, Inc: Consultancy, Honoraria. Buske:Hexal: Honoraria; Celltrion, Inc.: Consultancy, Honoraria; Pfizer: Honoraria; Gilead: Honoraria; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding. Ogura:SymBio: Consultancy, Research Funding; Celgene: Consultancy, Honoraria; Astrazeneca: Honoraria; Takeda: Consultancy, Honoraria; Mundipharma: Consultancy; MeijiSeika Pharma: Consultancy; Celltrion, Inc: Consultancy, Honoraria. Kwak:Celltrion, Inc: Consultancy; InnoLifes: Consultancy, Equity Ownership; Pepromene Bio: Consultancy, Equity Ownership. Lee:Celltrion, Inc: Employment. Bae:Celltrion, Inc: Employment. Kim:Celltrion, Inc: Employment. Kim:Celltrion, Inc: Employment. Lee:Celltrion, Inc: Employment. Kwak:Celltrion, Inc: Employment. Lee:Celltrion, Inc: Employment.

Post-Marketing Surveillance with a Biosimilar of Rituximab (Novex®) in Argentina

IntroductionNovex® is a biosimilar of Rituximab approved in Argentina having the same indications as the reference product (Mabthera®/Rituxan®). It is commercialized by Laboratorio Elea and since its commercial launch the first national pharmacovigilance plan for a Biosimilar mAb has been implemented.Material and MethodsIn order to detect deviations from expected frequencies of adverse events, a prospective treatment registry for NOVEX® was implemented since beginning of commercialization (November 26th, 2014). The Data Lock Point for this report is June 30th, 2017. Physicians registered the following information for each patient: age, gender, indication, dosing, dose frequency and date of treatment initiation and finalization. Treatment outcome and all Adverse Event detected were registered and coded using MedDRA dictionary.ResultsOne-hundred and eighty physicians have participated in this surveillance program. A total of 525 individual records, with at least 1 follow up point, were collected and included in analysis.The percentage of female patients was 52%. Age range was 10 - 90 years with a mean age of 63.3 years. The majority of patients have received NOVEX® due to a hematological disease (91.2% of cases) (table 1).Treatment duration ranged from 154 to 309 days (IQR), with mean of 239 days and median of 214 days. The number of cycles varied from 1 to 12 with a mean of 5.7.Twenty-four individual Case Safety Reports (ICSRs) were collected, with 29 Adverse Events, and the relative frequency of ICSR was 4.6%. Occurrence rates of adverse events were 1.2 per 100 administered cycles, and 0.022 per 100 treatment days. Fourteen serious adverse events (SAE) were collected and most of them were acute infusion related reactions.The most frequently reported AEs were:· Acute Infusion Related Reaction (14)· Arrhythmia (3)· Pneumonia (2)· Stroke (2)During the program, we detected 41 treatments with rituximab that were started before the launch of the product. Assuming these treatments had begun with Mabthera, this implies the occurrence of interchangeability in this subgroup.Because of the special interest of this condition, the frequency of ICSRs was analyzed. Two ICSRs were reported, with a relative frequency of 4.9 % (CI95%: 1.7 - 11.5%), which was similar to the whole frequency of the program. Therefore, it was considered that there were no significant differences in the level of reports in the group with interchangeability compared to the general group.ConclusionsThis post-marketing surveillance demonstrates a similar incidence of adverse events after the use of rituximab biosimilar when compared to the published data related to the reference product. Therefore, in terms of tolerability, this biosimilar product has a similar safety profile of that of the reference product. This data is consistent with the high similarity demonstrated during preclinical in vitro and in vivo characterization and the clinical efficacy and safety profile demonstrated in the comparative clinical trial. [Display omitted] DisclosuresPenna:Laboratorio ELEA: Employment. Fernández:Laboratorio ELEA: Employment. Spitzer:Laboratorio ELEA: Employment. Millan:mAbxience: Employment. Gomez:Laboratorio ELEA: Employment.

Evaluation of the Safety and Tolerability of Rapid Infusion of Biosimilar Rituximab Truxima® — the University College London Hospitals (UCLH) Experience

▪Rituximab is a chimeric anti-CD20 monoclonal antibody approved in the EU (MabThera®; Roche) and US (Rituxan®; Genentech) to treat non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukaemia (CLL).In April 2017 the first biosimilar rituximab (Truxima®; NAPP) was approved in the UK for all indications of the reference biologic. Its adoption is expected to deliver a significant reduction in treatment costs.Administration of rituximab is associated with infusion-related reactions (IRRs). The incidence of IRRs is greatest with the first infusion and decreases significantly with subsequent infusions.To reduce the risk of IRRs, manufacturers recommend that the first dose is gradually increased every 30 minutes in 50mg/hour increments to a maximum of 400mg/hour. For subsequent infusions gradually increase every 30 minutes in 100mg/hour increments to a maximum of 400mg/hour, known as standard subsequent rate infusion. This means a typical rituximab infusion can take 4-6 hours.If the first infusion is well-tolerated, it is now widespread practice to administer subsequent MabThera® doses as a rapid infusion over 90 minutes, whereby 20% of the dose is given over the first 30 minutes, with the remaining 80% over the following 60 minutes (Sehn et al, Blood 2007).Reverting to slower infusion rates with the introduction of biosimilar rituximab could adversely impact daycare unit capacity, nursing resource, appointment length, and patient satisfaction.AimThe aim of our study was to assess the safety of rapid infusion of Truxima® by reviewing infusion related adverse events in patients 1) switching from MabThera® 2) with previous exposure to MabThera® but last dose received over 6 months ago and 3) rituximab naïve patients.MethodIn May 2017 all patients were switched from MabThera® to Truxima® at UCLH, London. Truxima® doses given between 22nd May and 26th July 2017 were identified from the electronic prescribing system (Chemocare®). Infusion-related reactions were noted from nursing infusion records and graded using Common Terminology Criteria for Adverse Events version 4.03.Patients who had been receiving MabThera® as a rapid infusion continued at this rate with Truxima®. Those patients who had received only one prior dose of MabThera® at the standard first dose infusion rate received their first Truxima® dose as a rapid infusion.Patients who had not received MabThera® for over 6 months or were MabThera® naïve, received their first Truxima® dose at the standard first dose infusion rate. If well-tolerated, subsequent doses were given as a rapid infusion.All patients received premedication with paracetamol (acetaminophen) and antihistamine.ResultsTable 1 shows the patient characteristics, MabThera® and Truxima® infusion rates and infusion-related reactions.DiscussionThe results showed that rapid infusion of Truxima® was well-tolerated in all three groups of patients. Additionally, patients switching from MabThera® safely received their first Truxima® dose as a rapid infusion. One patient switching from MabThera® developed tachycardia during their first Truxima® dose at rapid infusion rate; however this patient was able to receive subsequent Truxima® doses with additional glucocorticoid pre-medication without IRRs.Grade 2 or 3 IRRs were observed with 8 first rate infusions (12%) and 4 of the patients have received further Truxima® doses so far. These patients received their next dose at standard subsequent infusion rate with glucocorticoid pre-medication without incident, and 2 of the patients have had further doses as a rapid infusion without an IRR. Updated results will be presented at the ASH meeting 2017.ConclusionThis study is the first reported post-marketing experience of rapid infusion of biosimilar rituximab and showed that patients can be safely switched from MabThera® to Truxima® without reverting to slower infusion rates. In addition patients who tolerated their first infusion rate of Truxima® were able to tolerate a rapid infusion rate with subsequent doses.These findings will facilitate the introduction of Truxima® at centres prescribing rituximab without adversely impacting resource utilisation or patient experience. [Display omitted] DisclosuresCheesman:Roche: Consultancy; Novartis: Consultancy; Napp: Consultancy; Amgen: Consultancy. Ardeshna:ADC Therapeutics: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Conference Expenses, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Conference Expenses. Townsend:Roche: Consultancy.

A Randomized, Double-Blind, Phase III Study Comparing Proposed Biosimilar Rituximab (RTXM83) Versus Reference Rituximab, Both in Combination with CHOP, in the First Line Treatment of Patients with Diffuse Large B-Cell Lymphoma (DLBCL)

Methods: RTXM83 is a proposed biosimilar developed by mAbxience S.A. to the reference medicine product rituximab (MabThera®/ Rituxan®). A prospective, multicenter, double-blind, randomized trial compared the efficacy in terms of non-inferiority, pharmacokinetics (PK), pharmacodynamics (PD), safety and immunogenicity of RTXM83 vs rituximab (Mabthera®/Rituxan®), both in combination with CHOP chemotherapy (RTXM83-CHOP vs R-CHOP), as first-line treatment in patients with previously untreated CD20+ Diffuse Large B Cell Lymphoma (DLBCL). Adults aged ≥18 and ≤65 years, with a disease stage of I (only with bulky disease) to IV according to the Cotswolds modification of the Ann Arbor classification, and ECOG performance status ≤2 were included, and randomized (1:1) to receive up to a total of six cycles of either RTXM83-CHOP or R-CHOP. Patients were stratified according to study center and age-adjusted IPI scores (0 versus 1), which are based on: disease stage, ECOG, and lactate dehydrogenase (LDH) levels.The primary endpoint was to assess the response rate (RR) (complete response + partial response) achieved after cycle 6 of treatment by the International Working Group (IWG) criteria. PK, PD, safety and immunogenicity were assessed as secondary study endpoints. For PK, the systemic exposure (AUC and Cmax) were assessed at Cycle 1 and steady-state at Cycle 6 using a population PK (Pop PK) model approach. The serum levels of CD20+/CD19+ cells for PD profile, and of anti-drug antibodies (ADA) for immunogenicity assessment were analysed at different time points: start of treatment (Cycle 1 Day 1, pre-dose), at Cycle 5 Day 1 (pre-dose), at Cycle 6 Day 21 and during the follow-up period: FU 1 (3 months after last dose of treatment) and follow-up 3 if available (9 months after last dose of treatment).Results: A total of 241 patients, 123 in the RTXM83-CHOP arm and 118 R-CHOP arm, from 58 sites in 12 countries were eligible. Demographic and baseline characteristics were well balanced between arms. A difference of 3.9% in the RR in favour of the RTXM83-CHOP arm was achieved in the per protocol population (RR: 84.7% vs 80.8% in RTXM83-CHOP and the R-CHOP arm, respectively). The lower bound of the 95% CI of this difference (-6.20% to 14.03%) was above the non-inferiority margin of -13% that was set for the study.The Pop PK comprised a total of 5341 samples from 251 patients. Geometric least square means ratios (GLSMR) with the 90% CI of RXTM83/rituximab were 99.2% (93.6-105) for AUC and 99.6% (93.9-105) for Cmax,sd at Cycle 1 whereas, at steady-state the GLSMR were 103% (98.5-107) for AUC and 104% (99.5-109) for Cmax,ss. RXTM83 and rituximab exhibited a comparable serum concentration-time profile and the GLSMR were within the predefined margins of 80-125%. PD profile in terms of time of onset, magnitude and duration of response was similar between RTXM83 and rituximab.Safety assessment shows no obvious differential safety profile of RXTM83 and rituximab in terms of nature, frequency and severity of the adverse events (AE); being infections and blood and lymphatic system disorders the most common SAEs reported.A low and similar ADA incidence was observed in both treatment arms, with no relationship with efficacy, safety or PK/PD data was observed.Conclusion: These results demonstrate that RTXM83 has comparable efficacy to rituximab in terms of tumour response, and displays a similar PK profile, PD activity, safety profile and immunogenicity in the first line treatment of patients with newly diagnosed DLBCL, which supports the claim that RTXM83 is highly similar to the reference medicine rituximab (MabThera® / Rituxan®). DisclosuresGonzalez:Lab Eticos: Other: Principal Investigator. Radhakrishnan:Cancer Institute Adyar Chennai India: Employment. Schusterschitz:Libbs: Research Funding. Perez:Mabxience SA: Employment.

Real-world overall response rate and other outcomes related to originator and biosimilar rituximabin patients with chronic lymphocytic leukemia or non-Hodgkin’s lymphoma in the United Kingdom.

e18696 Background: Rituximab is a chimeric anti-CD20 monoclonal antibody therapy, used primarily for treating chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphoma (NHL). Rituximab-abbs, the first rituximab biosimilar, was approved in the UK in 2017 and was expected to significantly reduce drug acquisition costs, but there is a lack of real-world evidence regarding patient outcomes with rituximab-abbs. This non-interventional study assessed the real-world effectiveness and tolerability of rituximab-abbs and rituximab in treatment-naive patients with CLL or NHL. Methods: Anonymized data on patient characteristics, response to treatment, healthcare resource utilization and costs were abstracted retrospectively via an online physician survey. UK-registered hematologists and oncologists reported on randomly selected patients aged ³18 years from four cohorts with documented CLL or NHL, who had received rituximab-abbs or rituximab as first-line immunotherapy (between January 1, 2018 and June 30, 2019). Patient outcomes data were provided from first treatment to the last date of follow-up available in the medical records. Results: In total, 46 physicians abstracted data from 201 patient charts. Demographic profiles of the cohorts were similar. For both treatments, the overall response rate (ORR) was very high for patients with CLL or NHL (Table) along with rates for six-month progression-free survival (96–98% across cohorts) and one-year survival (98–100% across cohorts). Most patients did not experience a grade ≥3 adverse event during treatment (54–66% across cohorts); the most common grade ≥3 adverse events were neutropenia, fatigue, anemia and infusion reactions. Healthcare resource utilization was similarly high across cohorts, driven by drug costs, diagnostic testing, oncologist office visits, and day case hospital admissions. Mean annual savings of approximately £1,000 per patient were seen with rituximab-abbs, attributable to first-line treatment costs. Conclusions: The originator (rituximab) and biosimilar (rituximab-abbs) products yielded comparable efficacy and tolerability in treating CLL and NHL in routine UK clinical practice, with rituximab-abbs demonstrating cost-savings. These findings should inform decision-makers on the potential for cost reductions where the biosimilar rituximab-abbs is available as a treatment alternative.[Table: see text]

U.S. budget impact analysis of an intravenousrituximab biosimilar versus subcutaneous rituximab for the treatment of non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL).

e18821 Background: Rituximab-abbs is a CD20-directed monoclonal antibody and the first rituximab biosimilar approved in the US, expected to significantly reduce drug acquisition costs. This budget impact model (BIM) estimated budgetary impact of replacing a proportion of rituximab/hyaluronidase human subcutaneous injection (SC-R) utilization for NHL (diffuse large B-cell lymphoma [DLBCL], follicular lymphoma [FL]) and CLL with rituximab-abbs (IV-R-BIOSIM). The objective was to project incremental cost differences between IV-R-BIOSIM and SC-R over one year for a hypothetical 5-million-member US healthcare insured (Medicare) population. Methods: An illustrative BIM was developed to estimate 1-year drug and administration costs for a one-quarter shift in SC-R market utilization to IV-R-BIOSIM, with equal efficacy and safety assumed. Values for epidemiology, market share, drug dosing, administration, and costs were derived from scientific literature, product labels, and publicly available cost resources. Infused rituximab (IV-R) dosing assumed a mean body surface area (BSA) of 1.8m2. Annual dose counts of IV-R-BIOSIM or SC-R per patient were: 10 untreated FL with maintenance; 8 untreated FL (without maintenance), relapsed/refractory FL, or untreated DLBCL; 6 CLL. IV-R infusion duration was 3 hours. Drug acquisition and infusion/subcutaneous administration costs were from 2020 Average Sales Price pricing file and Centers for Medicare and Medicaid Services Physician Fee Schedule. SC-R costs included an initial IV-R originator dose. Patient cost share was based on 2020 Medicare Part B 20% cost-share for office visits and drugs. Univariate sensitivity analyses were conducted. A scenario analysis used 2-year dosing to estimate costs for further FL maintenance treatment. Results: For a 5-million-member insured population, an estimated 972 patients would receive rituximab for NHL or CLL; 49 would receive SC-R. Estimated total incremental savings for one year for a 13-patient shift from SC-R to IV-R-BIOSIM were $57,864, equating to $0.02 per enrolled member per year (PMPY). Per-patient incremental annual savings with IV-R-BIOSIM for one year ranged between $2,359–$8,186 (Table). The model was most sensitive to low or high BSA dosing and proportion of patients with CLL. Conclusions: This BIM estimated annual savings of over $57,000 ($0.02 PMPY) for a 5-million-member US payer following a 25% shift of current SC-R use to IV-R-BIOSIM. These findings demonstrate the potential economic benefits of IV-R-BIOSIM vs SC-R that may result in expanded access to rituximab therapy.[Table: see text]