Combination Of Rituximab Research Articles

The FACT-targeted drug CBL0137 enhances the effects of rituximab to inhibit B-cell non-Hodgkin’s lymphoma tumor growth by promoting apoptosis and autophagy

BackgroundAggressive B-cell non-Hodgkin’s lymphoma (B-NHL) patients often develop drug resistance and tumor recurrence after conventional immunochemotherapy, for which new treatments are needed.MethodsWe investigated the antitumor effects of CBL0137. In vitro, cell proliferation was assessed by CCK-8 and colony formation assay. Flow cytometry was performed to analyze cell cycle progression, apoptosis, mitochondrial depolarization, and reactive oxygen species (ROS) production. Autophagy was detected by transmission electron microscopy and mGFP-RFP-LC3 assay, while western blotting was employed to detect proteins involved in apoptosis and autophagy. RNA-sequencing was conducted to analyze the transcription perturbation after CBL0137 treatment in B-NHL cell lines. Finally, the efficacy and safety of CBL0137, rituximab, and their combination were tested in vivo.ResultsCBL0137, a small molecule anticancer agent that has significant antitumor effects in B-NHL. CBL0137 sequesters the FACT (facilitates chromatin transcription) complex from chromatin to produce cytotoxic effects in B-NHL cells. In addition, we discovered novel anticancer mechanisms of CBL0137. CBL0137 inhibited human B-NHL cell proliferation by inducing cell cycle arrest in S phase via the c-MYC/p53/p21 pathway. Furthermore, CBL0137 triggers ROS generation and induces apoptosis and autophagy in B-NHL cells through the ROS-mediated PI3K/Akt/mTOR and MAPK signaling pathways. Notably, a combination of CBL0137 and rituximab significantly suppressed B-NHL tumor growth in subcutaneous models, consistent with results at the cellular level in vitro.ConclusionsCBL0137 has potential as a novel approach for aggressive B-NHL, and its combination with rituximab can provide new therapeutic options for patients with aggressive B-NHL.3a3Ge1vW8eA3YTTebu-sV5Video

Treatment Patterns and Health Care Costs in Commercially Insured Patients with Follicular Lymphoma.

BackgroundFew studies have estimated the real-world economic burden such as all-cause and follicular lymphoma (FL)-related costs and health care resource utilization (HCRU) in patients with FL.ObjectivesThis study evaluated outcomes in patients who were newly initiated with FL indicated regimens by line of therapy with real-world data.MethodsA retrospective study was conducted among patients with FL from MarketScan® databases between January 1, 2010 and December 31, 2013. Patients were selected if they were ≥18 years old when initiated on a FL indicated therapy, had at least 1 FL-related diagnosis, ≥1 FL commonly prescribed systemic anti-cancer therapy after diagnosis, and did not use any FL indicated regimen in the 24 months prior to the first agent. These patients were followed up at least 48 months and the outcomes, including the distribution of regimens by line of therapy, the treatment duration by line of therapy, all-cause and FL-related costs, and HCRU by line of therapy were evaluated.ResultsThis study identified 598 patients who initiated FL indicated treatment. The average follow-up time was approximately 5.7 years. Of these patients, 50.2% (n=300) were female, with a mean age of 60.7 years (SD=13.1 years) when initiating their treatment with FL indicated regimens. Overall, 598 (100%) patients received first-line therapy, 180 (43.6%) received second-line therapy, 51 received third-line therapy, 21 received fourth-line therapy, and 10 received fifth-line therapy. Duration of treatment by each line of therapy was 370 days, 392 days, 162 days, 148 days, and 88 days, respectively. The most common first-line regimens received by patients were rituximab (n=201, 33.6%), R-CHOP (combination of rituximab, cyclophosphamide, doxorubicin hydrochloride [hydroxydaunomycin]; n=143, 24.0%), BR (combination of bendamustine and rituximab; n=143, 24.0%), and R-CVP (combination of rituximab, cyclophosphamide, vincristine, and prednisone; n=71, 11.9%). The most common second-line treatment regimens were (N=180): rituximab (n=78, 43.3%) and BR (n=41, 22.8%). Annualized all-cause health care costs per patient ranged from US$97 141 (SD: US$144 730) for first-line to US$424 758 (SD: US$715 028) for fifth-line therapy.ConclusionsThe primary regimens used across treatment lines conform to those recommended by the National Comprehensive Cancer Network clinical practice guidelines. The economic burden for patients with FL is high and grows with subsequent lines of therapy.

REFLECT: prospective multicenter non-interventional study evaluating the effectiveness and safety of Sandoz rituximab (SDZ-RTX; Rixathon®) in combination with CHOP for the treatment of patients with previously untreated CD20-positive diffuse large B-cell lymphoma.

REFLECT is the first prospective study of Sandoz biosimilar rituximab (SDZ-RTX) in patients with diffuse large B-cell lymphoma (DLBCL). To evaluate the 2-year effectiveness and safety of SDZ-RTX as first-line treatment for DLBCL. Real-world, multicenter, open-label, single-arm, non-interventional, post-approval study of SDZ-RTX in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with treatment-naïve CD20‑positive DLBCL. Treatment-naïve, CD20-positive adult patients (⩾18 years) with DLBCL eligible for therapy with R-CHOP were treated with SDZ-RTX-CHOP every 2 or 3 weeks for 6-8 cycles. The effectiveness of SDZ-RTX was measured by the complete response (CR) rate at the end of R-CHOP treatment, as assessed by the treating physician. Progression-free survival (PFS) was assessed at 24 months. A total of 169 patients [52.1% female, median (range) age 70 (24-94) years] with DLBCL were included in the full analysis set. At baseline, 19.5% and 24.3% of patients had Ann Arbor disease stage III or IV, respectively, and most patients (80.5%) had Eastern Cooperative Oncology Group Performance Status of 0 or 1. A total of 100 (59.2%) patients completed the 24-month observation period. In total, 110 [65.1%; 95% confidence interval (CI): 57.4-72.3] patients achieved CR as best response and 50 (29.6%; 95% CI: 22.8-37.1) patients achieved partial response. Overall best response rate was 94.7% (95% CI: 90.1-97.5). One-year PFS was 84.9% (95% CI: 78.2-89.6), while 2-year PFS was 78.5% (95% CI: 70.9-84.4); median PFS was not reached within the observational period. A total of 143 (84.6%) patients experienced ⩾1 adverse event, 53 (31.4%) of which were suspected to be related to study drug. This real-world, 2-year study reconfirms that first-line treatment of CD20-positive DLBCL with R-CHOP using SDZ-RTX is effective and well tolerated. N/A.

Severe eosinophilic granulomatosis with polyangiitis responding to a combination of rituximab and mepolizumab.

Eosinophilic granulomatosis with polyangiitis (EGPA), formerly known as Churg-Strauss Syndrome, is a multisystem antineutrophil cytoplasmic antibody (ANCA) positive vasculitis, characterized by the presence of chronic rhinosinusitis, asthma and prominent peripheral blood eosinophilia. Although the most commonly involved organ is the lung, followed by the skin, EGPA can affect any organ system. Herein, we present the complicated case of an 18-year-old male patient with severe life-threatening EGPA, with central nervous system, cardiac and gasterointestinal involvement, which was resistant to initial treatment with glucocorticoids and cyclophosphamide. The patient responded well, achieving complete remission after the addition of rituximab and mepolizumab to glucocorticoids and cyclophosphamide.

Identification of biomarkers to stratify response to B-cell-targeted therapies in systemic lupus erythematosus: an exploratory analysis of a randomised controlled trial.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease associated with widespread immune dysregulation and diverse clinical features. Immune abnormalities might be differentially associated with specific organ involvement or response to targeted therapies. We aimed to identify biomarkers of response to belimumab after rituximab to facilitate a personalised approach to therapy. In this exploratory analysis of a randomised controlled trial (BEAT-LUPUS), we investigated immune profiles of patients with SLE recruited to the 52-week clinical trial, which tested the combination of rituximab plus belimumab versus rituximab plus placebo. We used machine learning and conventional statistics to investigate relevant laboratory and clinical biomarkers associated with major clinical response. BEAT LUPUS is registered at ISRCTN, 47873003, and is now complete. Between Feb 2, 2017, and March 28, 2019, 52 patients were recruited to BEAT-LUPUS, of whom 44 provided clinical data at week 52 and were included in this analysis. 21 (48%) of 44 participants were in the belimumab group (mean age 39·5 years [SD 12·1]; 17 [81%] were female, four [19%] were male, 13 [62%] were White) and 23 (52%) were in the placebo group (mean age 42·1 years [SD 10·5]; 21 [91%] were female, two [9%] were male, 16 [70%] were White). Ten (48%) of 21 participants who received belimumab after rituximab and eight (35%) of 23 who received placebo after rituximab had a major clinical response at 52 weeks (between-group difference of 13% [95% CI -15 to 38]). We found a predictive association between baseline serum IgA2 anti-double stranded DNA (dsDNA) antibody concentrations and clinical response to belimumab after rituximab, with a between-group difference in major clinical response of 48% (95% CI 10 to 70) in patients with elevated baseline serum IgA2 anti-dsDNA antibody concentrations. Moreover, among those who had a major clinical response, serum IgA2 anti-dsDNA antibody concentrations significantly decreased from baseline only in the belimumab group. Increased circulating IgA2 (but not total) plasmablast numbers, and T follicular helper cell numbers predicted clinical response and were both reduced only in patients who responded to belimumab after rituximab. Serum IgA2 anti-dsDNA antibody concentrations were also associated with active renal disease, whereas serum IgA1 anti-dsDNA antibody and IFN-α concentrations were associated with mucocutaneous disease activity but did not predict response to B-cell targeted therapy. Patients with a high baseline serum interleukin-6 concentration were less likely to have a major clinical response, irrespective of therapy. This exploratory study revealed the presence of distinct molecular networks associated with renal and mucocutaneous involvement, and response to B-cell-targeted therapies, which, if confirmed, could guide precision targeting of advanced therapies for this heterogenous disease. Versus Arthritis, UCLH Biomedical Research Centre, LUPUS UK, and GSK.

Pathobiology and its clinical relevance in diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is a clinically and biologically heterogeneous disease. Remarkable effort has been exerted in the classification of DLBCL and the development of its corresponding treatment. The prognosis of patients with DLBCL receiving rituximab combination chemotherapy significantly improved in the early 2000s. However, approximately 40% of patients still develop recurrence, and the prognosis of these patients is extremely poor. Recently, the use of polatuzumab vedotin and CAR T-cell therapies has improved patient prognosis. However, it is extremely important to identify the patient group who can benefit from the efficacy of these treatments. In relation to this, the molecular pathogenesis of DLBCL should be further evaluated. Recent advancements in the genetic analysis technology have led to the discovery of unknown genetic abnormalities and gene expression patterns. The elucidation and subdivision of the molecular pathology based on these findings will be the foundation of future personalized medicine.

The iR2 regimen (ibrutinib plus lenalidomide and rituximab) for relapsed/refractory DLBCL: a multicentre, non-randomised, open-label phase 2 study

This phase 1b/2 PCYC-1123-CA study evaluated efficacy and safety of the combination of ibrutinib, lenalidomide, and rituximab (iR2 regimen) in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) ineligible for stem cell transplantation. In phase 2, patients with relapsed/refractory non-germinal centre B-cell-like DLBCL received oral ibrutinib 560mg once daily and oral lenalidomide 20mg or 25mg once daily on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity and intravenous rituximab 375mg/m2 on Day 1 of Cycles 1-6. The primary endpoint was overall response rate (ORR) in the response-evaluable population (received any study treatment and had ≥1 post-baseline disease assessment). The study was done at 24 academic and community hospitals in Belgium, Germany, United Kingdom, and USA. This study was registered with ClinicalTrials.gov, NCT02077166. Between March 13, 2014 and October 2, 2018, 89 patients were enrolled with a median time on study of 35.0 months. Best ORR in the response-evaluable population (n=85) was 49% (95% confidence interval [CI], 38-61) across dose cohorts and 53% (95% CI, 39-67) and 44% (95% CI, 26-62) in the 20mg and 25mg lenalidomide cohorts, respectively, with complete responses in 24/85 (28%), 17/53 (32%), and 7/32 (22%) patients, respectively. Grade 3/4 adverse events (AEs) occurred in 81/89 patients (91%), most frequently neutropenia (36/89; 40%), maculopapular rash (16/89; 18%), anaemia (12/89; 13%), and diarrhoea (9/89; 10%). Serious adverse events occurred in 57/89 patients (64%). Fatal AEs occurred in 12/89 patients (13%); causes of death were worsening of DLBCL (n=7), pneumonia (n=3), sepsis (n=1), and cardiac arrest (n=1). The most frequent AEs (diarrhoea, neutropenia, fatigue, cough, anaemia, peripheral oedema, and maculopapular rash) were consistent with known safety profiles of the individual drugs. The iR2 regimen demonstrated antitumour activity with durable responses in patients with relapsed/refractory DLBCL. Pharmacyclics LLC, an AbbVie Company.

Lymphoplasmacytic Lymphoma with Paraprotein IgG

Lymphoplasmacytic lymphoma (LPL) is a rare indolent mature B-cell lymphoma. LPL secreting immunoglobulins other than IgM are rare. There are very few case series on non-IgM LPL, and little is known about the clinical features and outcomes of patients with this disease. We report the case of a 65-year-old-male who was referred to our hospital for further investigations of persistent chronic anaemia and was diagnosed with IgG-LPL based on the presence of M protein from serum electrophoresis. Bone marrow morphology exhibit a spectrum of B-cell differentiation ranging from small mature lymphocytes to plasma cells. The patient underwent treatment with a combination of bortezomib, dexamethasone and rituximab and showed positive response. LPL with paraprotein IgG is a rare indolent disease and has a heterogeneous clinicopathological presentation with limited literature reviews. Our case report and literature review provide insights and knowledge in the description of the clinicopathological features of IgG LPL.

Effectiveness of Different Rituximab Doses Combined with Leflunomide in the Treatment or Retreatment of Rheumatoid Arthritis: Part 2 of a Randomized, Placebo-Controlled, Investigator-Initiated Clinical Trial (AMARA).

The optimal dose of rituximab in combination with leflunomide in patients with rheumatoid arthritis (RA) is not known. In Part 1 (previously reported) of the investigator-initiated AMARA study (EudraCT 2009-015950-39; ClinicalTrials.gov NCT01244958), improvements at week (W)24 were observed in patients randomized to rituximab + leflunomide compared with placebo + leflunomide. In the study reported here (Part 2), Part 1 responders received rituximab 500 or 1000 mg at W24/26 plus ongoing leflunomide. Patients were randomized at baseline to their eventual W24 treatment group. The Part 2 primary outcome was the mean Disease Activity Score-28 joints (DAS28) at W52, based on the last observation carried forward (LOCF) analyses and a two-sided analysis of variance. Patient-reported outcomes (PROs) and adverse events were evaluated. Eighty-three patients received rituximab at W24/26 (31 rituximab→rituximab 1000 mg; 29 rituximab→rituximab 500 mg; 10 placebo→rituximab 1000 mg; 13 placebo→rituximab 500 mg). At W52, there were no significant differences in DAS28 between rituximab doses in patients originally treated with rituximab or those originally treated with placebo. In the Part 1 placebo group, the higher rituximab dose was associated with greater improvements in ACR response rates and some PROs. Adverse events were similar regardless of rituximab dose. Retreatment with rituximab 500 mg and 1000 mg showed comparable efficacy, whereas an initial dose of rituximab 500 mg was associated with lower response rates versus 1000 mg. Reduced treatment response with the lower dose in patients initially treated with placebo may have been influenced by small numbers and baseline disease activity.

ML-5 THE TRANSITION OF THE TREATMENT OF 60 PCNSL CASES AT OUR INSTITUTION AND CLINICAL CONSIDERATIONS

Abstract The efficacy of RMPV-A (rituximab, methotrexate, procarbazine, vincristine, and cytarabine) and whole brain irradiation for primary central nervous system lymphoma (PCNSL) have recently been reported. Our institution also introduced RMPV therapy in 2020 after an era of conventional HD-MTX to cytarabine and rituximab combination. In this report, we analyzed 60 PCNSL cases treated from 2013 to 2021.There were 32 female patients (53%) with a median age of 70 years (30-87). Five patients (8%) received radiotherapy alone as initial treatment, 30 (50%) received HD-MTX (including radiation), 17 (28%) received HD-MTX plus rituximab or cytarabine, and 9 (13%) received RMPV therapy. The response rate (CR, CRu, PR) in the HD-MTX group was 88%, and the complete response rate (CR, CRu) was 51%. In contrast, the RMPV arm had a response rate of 100% and a complete response rate of 6 patients (66.7%). 7 patients (14%) in the HD-MTX arm and 2 patients (22%) in the RMPV arm were unable to continue treatment due to adverse events. The treatment of PCNSL has undergone significant changes in recent years, with the availability of RMPV-A, thiotepa, and tirabrutinib, and it is now possible to construct treatment that avoids leukoencephalopathy caused by radiation therapy as much as possible, which had been a major problem of conventional therapy. However, because of the use of strong drugs, caution must be exercised when treating patients in poor general conditions, especially the elderly. However, the present analysis indicates that many elderly patients can be successfully treated with careful observation. In the future, it is essential to accumulate cases treated with RMPV therapy and tilabrutinib and conduct further data analysis to establish a new generation of treatment for PCNSL.

Rituximab Monotherapy versus Rituximab and Bortezomib Combination Therapy for Treatment of Non-paraneoplastic Autoimmune Retinopathy.

To study whether rituximab and bortezomib combination therapy is more effective than rituximab monotherapy in the treatment of non-paraneoplastic autoimmune retinopathy (npAIR). Retrospective case series involving six patients with npAIR, taking either rituximab and bortezomib combination therapy (three cases) or rituximab monotherapy (one case and two historical patients). Patients on both treatment regimens showed stability in most of the visual function parameters during the one year of follow-up. Combination therapy resulted in improvement of scotopic combined rod and cone a-wave and b-wave amplitudes in all eyes where they were available (four eyes); however, rituximab monotherapy resulted in only two eyes with stable scotopic combined rod and cone a-wave and b-wave amplitudes, while four eyes showed a decrease in both a- and b-wave amplitudes. The average improvement in b-wave amplitude (50.7% 29.4% [range, 25-90%]) was higher than the average improvement in a-wave amplitude (35.7% 9.74 [range, 25-63%]). No severe adverse effects were reported. Rituximab and bortezomib combination therapy may not be more effective than rituximab monotherapy in npAIR patients for most of the visual function parameters; however, this combination therapy may be more effective in improving scotopic combined rod and cone a- and b-wave amplitudes. This may indicate the higher efficacy of combination therapy when there is involvement of the inner retina.

Polatuzumab vedotin, rituximab, and bendamustine combination in relapsed or refractory diffuse large B-cell lymphoma: a real-world data from Turkey.

Polatuzumab vedotin (Pola) with bendamustine and rituximab (BR) is a promising option for patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). We analyzed the data of 71 R/R DLBCL patients who had been treated with Pola-BR in the named patient program from March 2018 to April 2021 from 32 centers in Turkey. All patients received up to six cycles of Pola 1.8mg/kg, rituximab 375mg/m2 on day 1, and bendamustine 90mg/m2 on days 1-2 of each cycle. Median age at Pola-BR initiation was 55 (19-84). The overall response rate was 47.9%, including 32.4% CR rate when a median of 3 cycles was applied. With a median follow-up of 5months, the median OS was 5months. Grade 3-4 neutropenia and thrombocytopenia were the most common hematological toxicities. The real-world data from our cohort showed the Pola-BR is an effective option with a manageable toxicity profile.

Rituximab Use in Relapsed Indolent B-Cell Lymphoma: Real-World Data (RWD) Analysis Using Healthcare Claims Databases

Introduction: Rituximab as monotherapy or in combination with chemotherapy has been the mainstay for treatment of indolent B-cell non-Hodgkin lymphoma (iNHL) in clinical practice for 25 years. Patients with disease who progress <6 months from prior rituximab treatment are considered refractory and may be best treated with a treatment modality other than the initial one. Patients progressing >12 months from prior rituximab treatment are considered rituximab-sensitive and may be candidates for retreatment either with rituximab monotherapy or with arituximab-based combination. To gain a better understanding of rituximab use in clinical practice in patients with relapsed iNHL, rituximab prescriptions from two large national-level health claims databases were analyzed and rituximab usage in patients with a treatment-free interval of a minimum of 180 days between the end of the first treatment and the start of the second treatment was identified. Methods: This is a retrospective cohort study based on 2 large US claims databases: Optum Clinformatics (DB1) and Marketscan Commercial (DB2). Adult patients (≥18 years old) with at least one claim for a diagnosis of B-cell NHL (FL, MZL, SLL, WM/LPL) between July 1, 2007 and January 1, 2020 were identified using ICD-9 and ICD-10 codes. Patients had to have continuous insurance eligibility with medical and pharmacy benefit coverage from 12 months prior to diagnosis of iNHL until at least 90 days after the start of the second treatment with rituximab monotherapy or combination. Relapse was defined as a treatment-free period of at least 180 days between the end of the first rituximab-based treatment and the start of the second rituximab-based treatment. Patients were categorized into two groups based on whether patients received rituximab as monotherapy or as combination therapy after relapse. Results: From July 2007 to January 2020, a total 13,037 patients from DB1 and 23,590 patients from DB2 were diagnosed with iNHL and received first rituximab-based treatment, 3731 (29%) and 7153 (30%), respectively, as monotherapy and 9306 (71%) and 16,437 (70%) in combination. Of those receiving first rituximab-based treatment, 1050 (28%) patients from DB1 had a treatment-free interval of ≥180 days from the end of the first rituximab-based treatment to the start of the second rituximab-based treatment, of whom 596 (57%) received rituximab as monotherapy and 454 (43%) in combination. Similarly, of those receiving first rituximab-based treatment in DB2, 1780 (25%) patients had a treatment-free interval of ≥180 days from the end of the first rituximab-based treatment to the start of the second rituximab-based treatment, of whom 1131 (64%) received rituximab monotherapy and 649 (36%) in combination. Further exploration of patient characteristics for patients receiving rituximab monotherapy as retreatment for relapsed iNHL are shown in Table. Patients were slightly older in DB1, but otherwise the treatment patterns were similar for both databases. Patients receiving rituximab combination therapy as retreatment had a longer treatment-free interval compared to patients receiving rituximab monotherapy after relapse in both databases. Likewise, patients with a treatment-free interval of >6 month but <12 months were more likely to receive rituximab monotherapy after relapse, whereas those with a treatment-free interval of ≥12 months were more likely to receive rituximab-based combination. Conclusions: The rituximab treatment patterns for relapsed iNHL were markedly consistent across two large US claims databases despite differences in the two commercially insured populations. Based on these RWD, rituximab combinations were more frequently prescribed as initial treatment, while rituximab monotherapy was more commonly prescribed in the relapsed setting. However, in the relapsed setting, if the treatment-free interval was >12 months, then rituximab-based combinations were more frequently prescribed. This study provides useful insights for clinicians into real-world treatment patterns. Future research should examine clinical response to various rituximab-based treatments in relapsed setting. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Early Treatment with Ofatumumab in Patients with High-Risk CLL

Introduction Early treatment initiation for patients with high-risk CLL has not been shown to be associated with clinical benefit in studies utilizing rituximab and rituximab in combination with alemtuzumab. Ofatumumab is a fully human monoclonal antibody targeting CD20. It is well-tolerated and has improved target binding and cytotoxicity compared to rituximab. We therefore sought to evaluate the efficacy of ofatumumab as early treatment in patients with high-risk CLL. Methods This was a single-arm, open label, phase II trial for treatment-naïve, watch-and-wait patients with high-risk for progression to need treatment. Based on currently available models, high-risk CLL was defined as presence of one or more of the following: Rai stage 2 disease or Rai stage 0-1 with disease related fatigue, β2M ≥ 3mg/L, ALC ≥ 25K/µL, unmutated IGHV, ZAP70-positive, CD38-positive, or FISH with del(11q) or del(17p). Patients who met 2008 iwCLL criteria for treatment were excluded. The primary objective was overall response rate (ORR) with secondary objectives of progression-free survival (PFS), time-to-next treatment (TTNT), and overall survival (OS). Treatment consisted of a total of 8 weekly doses of ofatumumab. The first weekly dose was 300mg to reduce infusion reactions, subsequently ofatumumab 1000mg was then administered weekly for 7 weeks. Results Between 04/2011 and 06/2015, 44 pts were enrolled in the study and initiated treatment. The median age at study entry was 60 years with a median time from diagnosis to study entry of 15.3 mo. The median ALC, HGB and PLT counts were 20.1K/µL, 14mg/dL, and 166K/µL, respectively. The median LDH was 481U/L (range 345 - 855). When characterized based on FISH alterations, 19(43%) pts had del(13q), 7(16%) pts had trisomy 12, 8(18%) pts had del(11q), 3(7%) pts had del(17p), and 7(16%) pts had no abnormalities. When characterized based on other high-risk features: 24(55%) pts had unmutated IGHV, 21(48%) pts were ZAP70(+), 15(34%) pts were CD38(+), 6(14%) had elevated β2M, and 21(48%) had an ALC over 25K/µL. The ORR to ofatumumab (complete + partial remission) was 63% with 3(7%) pts attaining undetectable MRD status at 10-4 sensitivity. At a median follow up of 8 years, the median PFS, TTNT, and overall survival (OS) were 16.3 mo, 42.8 mo, and not reached. Thirty (68%) pts went on to receive further treatment (19 pts on BTK based regimens, 2 pts received venetoclax monotherapy, 5 pts received combined venetoclax and ibrutinib, 3 pts received chemoimmunotherapy, and 1 pt received obinutuzumab monotherapy). This regimen of early treatment with ofatumumab was well tolerated. The most common adverse reaction was infusion reactions occurring in 16 pts (36%) with all reactions being amendable to antihistamine and/or steroid treatment. In all of these pts the infusion was restarted. One pt had to discontinue ofatumumab treatment after the second infusion due to autoimmune hepatitis. Conclusion In a population of patients with CLL at high-risk for proceeding to treatment, early treatment with ofatumumab resulted in a PFS and TTNT of 16.3 mo and 42.8 mo, respectively. The PFS was similar to that of similarly designed trials with rituximab monotherapy and rituximab in combination with alemtuzumab, respectively. Further internal matched analysis is being conducted to compare time to second treatment. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Survival of Patients with Primary Mediastinal B-Cell Lymphoma Treated By Immunochemotherapy with or without Radiotherapy

Introduction: Primary mediastinal B-cell lymphoma (PMBL) is B-non-Hodgkin lymphoma subtype with unique clinical and biological characteristics mostly affecting younger patients. The current treatment standard is based on combination of rituximab and anthracycline based chemotherapy (R-CHT), either standard (R-CHOP) or intensified (DA-EPOCH-R). Radiotherapy (RT) consolidation has been standard of care for a long time, but its role is currently unclear, especially in the context of PET/CT guided therapy and long term toxicity prevention considering young patient population (Hayden at al.2020, Giulino-Roth 2018). In this analysis we evaluate the survival benefit of RT consolidation in patients with PMBL achieving PET negative (PET-neg) response after R-CHT. Methods: Patients with confirmed diagnosis of PMBL observed in NiHiL project (Gov Trial No: NCT03199066) were analysed. All patients were treated by R-CHT; PET/CT was performed at the end of the immunochemotherapy. The treatment response was evaluated according to Cheson 2007 criteria. Only patients achieving PET negativity were included in primary analysis. Results: The study included 230 patients out of whom 133 (57.8%) were women. Median age was 37 years (range 19-79); localised stage (I-II) was observed in 165 patients (71.7%) and low or low-intermed IPI in 189 patients (82.2%). The diagnosis was confirmed by central pathologist in all cases. Patients were treated by R-CHT, mostly R-CHOP (52.2%) and R-CHOEP-like (25.2%; i.e. R-CHOEP or DA-EPOCH-R); other intensive regimens, incl. platinum were used in 19.6% of patients; 48 patients (20.8%) received ASCT as part of first line induction. PET/CT was performed at the end of R-CHT (including ASCT); 174 patients (75.7%) achieved PET-neg remission at the end of the immunochemotherapy, 56 (24.3%) were PET positive (PET-pos). After reaching PET negativity, radiotherapy was performed in 68 patients (39.1%) with median dose of 36Gy (range 20-42Gy); 106 patients were not consolidated by RT and observed (OBS). There was higher incidence of bulky disease and B-symptoms in RT group (57% vs 47% and 57% vs 48% resp.) without reaching statistical significance. Median follow up was 5.9 years. OS and PFS probability at 6y were 90.5% and 83.6% resp. for the whole cohort. RT consolidation in PET-negative subgroup led to a significant improvement (p=0.039) in PFS at 6y with 95% (n=68) vs 85.3% in OBS group (n=106). This was, however, not transformed into the OS difference (94.5% vs 92.1% probability at 6y for RT vs OBS; HR 1.64, CI95% 0.52-5.8), figure 1. In subgroup of patients treated by R-CHOP, there was an insignificant trend for better PFS probability in RT group (HR 2.41, 95%CI 0.71-6.92, p=0.17). This was not reflected in any OS difference. The outcome of patients who reached PET negativity by R-CHOEP was the same regardless of the radiotherapy use. Conclusion: Our analysis of retrospectively recorded patients shows that skipping RT in PET-neg PMBL patients at the end of immunochemotherapy does not hamper overall survival. There was borderline improvement of PFS. The patient cohorts with different chemotherapy regimens were not big enough to analyse the RT significance. However, data observed in patient subpopulation treated by CHOEP-like regimen confirm already published observations (Dunleavy et al. 2013) concluding possible RT oblivion after intensified immunochemotherapy. Therefore, the choice between radiotherapy consolidation vs observation in PET negative patients should be discussed with the patient especially when less intensive regimen (R-CHOP) is used. Acknowledgement: This work was supported by Cooperatio Program - research area Oncology and Hematology and by research grant NU21-03-00411 Figure 1. Survival analysis of patients reaching PET negative remission after chemotherapy (n=174) shows improvement in progression free survival (PFS) for patients consolidated with radiotherapy (RT), however without reflection in overall survival (OS). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

SUNMO: A Phase III Trial Evaluating the Efficacy and Safety of Mosunetuzumab in Combination with Polatuzumab Vedotin Versus Rituximab in Combination with Gemcitabine Plus Oxaliplatin in Patients with Relapsed or Refractory Aggressive B-Cell Non-Hodgkin Lymphoma

SUNMO: A Phase III Trial Evaluating the Efficacy and Safety of Mosunetuzumab in Combination with Polatuzumab Vedotin Versus Rituximab in Combination with Gemcitabine Plus Oxaliplatin in Patients with Relapsed or Refractory Aggressive B-Cell Non-Hodgkin Lymphoma

Rituximab Infusion in 30 Minutes’ Is Safe and Improves the Flow of Outpatients with Lymphoma Treatment (SPEEDR)

Rituximab is a chimeric monoclonal antibody approved to treat B cell non-Hodgkin's lymphoma. Infusion reactions among patients are common during the first exposure but decrease with subsequent infusions. During the COVID-19 pandemic, there was an urgent need to avoid crowding of patients at our outpatient clinic at Karolinska University Hospital. We therefore introduced a new schedule for rapid IV infusion of 30 minutes of rituximab (SPEEDR) to patients who had well tolerated at least one dose of IV rituximab given in 90 minutes. We here present a retrospective analysis of tolerance and side effects for patients treated between January 2021 and December 2021. Ninety-nine patients received a total of 190 doses of rapid 30 minute infusion of rituximab. Fifty eight (59%) were male and the median age of our patients was 73 years. The patients had different types of lymphoid malignances and the most common diagnoses were diffuse large B-cell lymphoma (DLBCL, 38%), follicular lymphoma (FL, 21%) and marginal zone lymphoma (MZL, 11%). Thirty-four patients received single-agent rituximab treatment whereas 65 received rituximab in combination with chemotherapy. The 30 minute infusion was given after a preceding well-tolerated 90 minute dose. All doses thereafter were administrated in 30 minutes if no adverse events > grades 1 were seen. Rituximab was diluted in 500 ml 0.9% sodium chloride and infused in 30 minutes IV with a steady infusion rate without ramp up. The treating nurse measured blood pressure and pulse before starting the infusion and after completed infusion for all patients. Temperature was monitored before starting infusion and if the patient felt any discomfort during treatment or after. Data on infusion reactions, blood pressure, temperature and pulse were extracted from each patient's journal. Statistical analysis was performed using STATA. During the study period only 3 patients experienced an infusion reaction during or after the 30 minute infusion. No reaction was more than grade 2 and all patients responded well to standard treatment with fluids and could complete the rituximab infusion. Two of the patients who had an adverse event had not received any steroids before rituximab, one was treated with R-CHOP and had ingested 100 mg prednisone as part of the regimen. Analysis of median values before and during infusion for pulse was 70 vs 71.5 BPM (p=0.16), blood pressure 119/71 vs 119/70 (p= 0.08) mm Hg. Given the long serum half time of rituximab, the rapid SPEEDR infusion is highly unlikely to have negative effects on efficacy. We conclude that rituximab given as a 30-minute IV infusion is feasible and safe for patients with lymphomas who have previously tolerated a 90 minute infusion. This is an efficient way to optimize work flow in the outpatient clinic and to give cost-effective treatment to lymphoma patients.

A Phase 2, Open-Label Study of Loncastuximab Tesirine in Combination with Rituximab (Lonca-R) in Previously Untreated Unfit/Frail Patients with Diffuse Large B-Cell Lymphoma (DLBCL) (LOTIS-9)

Background: Rituximab in combination with chemotherapy (R [rituximab]-CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisone]) is the standard first-line therapy for patients with DLBCL. With an aging population, unfit or frail patients who may not tolerate R-CHOP represent an increasing unmet need. There is also significant heterogeneity in how fitness for therapy is assessed. The simplified geriatric assessment (sGA) identifies three distinct categories (fit, unfit, and frail) based on age, activities of daily living (ADL), instrumental activities of daily living (IADL), and the Cumulative Illness Rating Scale for Geriatrics (CIRS-G, J Clin Oncol 2021;39(11):1214-1222). Loncastuximab tesirine (loncastuximab tesirine-lpyl; Lonca), an antibody-drug conjugate comprising a humanized anti-CD19 monoclonal antibody conjugated to a pyrrolobenzodiazepine dimer toxin, is approved in relapsed or refractory (R/R) DLBCL based on data from the phase 2 LOTIS-2 pivotal trial (Lancet Oncol 2021;22(6):790-800). The safety and efficacy of Lonca-R in combination is also being studied in patients with R/R DLBCL versus immunochemotherapy in an ongoing, separate study (LOTIS-5; NCT04384484). Objectives: To determine the safety and efficacy of Lonca-R in previously untreated unfit/frail patients with DLBCL, as characterized by the sGA, in the LOTIS-9 clinical trial (NCT05144009). Methods: This is a phase 2, open-label, response-adapted study of Lonca-R in previously untreated unfit (Cohort A) or frail (Cohort B) patients with DLBCL. Key inclusion criteria include diagnosis of DLBCL (including DLBCL transformed from indolent lymphoma), high-grade B-cell lymphoma, or grade 3b follicular lymphoma; Eastern Cooperative Oncology Group performance status of 0-2; and measurable disease (2014 Lugano Classification). Each cohort will enroll 40 patients, with fitness (Cohort A) and frailty (Cohort B) assessed using the sGA. The primary objectives are to assess efficacy (Cohorts A and B) and tolerability (Cohort B) of Lonca-R. The primary endpoint will be the complete response (CR) rate (Cohorts A and B) and tolerability defined by the percentage of patients completing a total of 4 cycles of therapy (Cohort B). Lonca-R treatment consists of R intravenously (IV) 375 mg/m2 on day 1 of cycles 1-4 (subcutaneously allowed starting at C2), Lonca 150 µg/kg IV on day 2 of cycle 1 and day 1 of cycle 2, and Lonca 75 µg/kg IV on day 1 of cycles 3 and 4. After completion of 3 Lonca-R cycles, patients who achieve CR or partial response (PR) will continue to receive 1 or 3 additional cycles of Lonca-R, respectively. Patients in Cohort A who do not achieve a CR or PR will discontinue study treatment. Patients in Cohort B who achieve stable disease and derive clinical benefit, per the treating physician, may continue to receive an additional 3 cycles of Lonca-R. All patients will be followed every 12 weeks for 1 year, every 24 weeks for up to 3 years, and then annually for up to 5 years. Results: The study is currently enrolling patients in the United States and will be available to centers in additional countries in the coming months, including Spain, Italy, and Israel. Funding: ADC Therapeutics SA; medical writing: CiTRUS Health Group.

Clinical Characterization, Prognosis and Therapeutic Management of 181 Patients with Splenic Marginal Zone Lymphoma (SMZL): Real World Experience of the Geltamo Group

Introduction: Splenic Marginal Zone Lymphoma (SMZL) is an uncommon subtype of non-Hodgkin Lymphoma, therefore, the data concerning the diagnosis, prognosis and treatment are scare and mostly based on a limited number of retrospective series. In 2014, GELTAMO group launched a guidelines for practical management of SMZL to be used in the everyday practice in this nation-wide network of collaborative hospitals. (GEL-LZME-2014-14). These Guidelines proposed/suggested different treatment strategies according to the HPLLs/ABC score (Montalban et al, 2012). Therapeutic recommendations were observation (W&W) in group A, rituximab in group B and rituximab in combination with chemotherapy (R-Chemotherapy) in group C. The primary endpoint was to analyze compliance with the guidelines and to evaluate the outcome according to the HPLLs/ABC-adapted therapeutic strategy in the real life. Methods: Observational multicenter study of patients with diagnostic of SMZL between 2014 and 2019 included prospectively and consecutively in the RELINF registry by Spanish GELTAMO centers. Clinical data at diagnosis, HPLLs/ABC prognostic index, treatment, response and follow up were obtained from the medical records and entered into a database. Lymphoma Specific Survival (LSS) and response rates according to treatment received were assessed in this study. Composite event free survival (CEFS) defined as death, histological transformation (HT), recurrence/progression under treatment, and need for treatment under observation, was also analyzed. HT was considered as a time-dependent event. Results: A total of 181 patients (84M/97F; median age 71 years) from 22 centers were included. The main initial characteristics of the patients are shown in Table 1. Splenectomy was performed in 17 cases (9%). 57% of the patients followed the recommendation of the GELTAMO Guidelines. 13 cases were excluded for response and survival analyses (i.e., 3 with HT at diagnosis, 5 treated for hepatitis C virus and 5 managed with palliative care). At diagnosis 77 patients (45%) received some therapy while 96 (55%) remained on W&W (Table 1). The overall response rate was higher in the R-Chemotherapy arm and in the Rituximab arm compared to splenectomy (p<0.001), with no significant differences between Rituximab and R-Chemotherapy. With a median follow up of 41.2 months, the 5-year overall survival (OS) of the whole series was 77%, and the 5-year LSS of 93%, with 32 patients (18%) dying, but only 13 (40%) due to the lymphoma or its treatment. 5-year LSS was 98% and 87% for score A and B, respectively (p=0.048), but unexpectedly, there were no deaths among the 9 patients of score C (5-year LSS: 100%). There were no differences in the 5-year LSS according to the treatment received in the overall series (p=0.68) (Figure 1), nor when scores A and B were analyzed separately. The 5-year CEFS in the overall series was 46%. Analyzing the composed event according to score, there were significant differences in terms of the 5-year CEFS between scores A and B (p=0.044). When comparing LSS and progression-free survival (PFS) in patients treated with Rituximab or R-Chemotherapy at diagnosis or after the W&W period, there were no significant differences between the two groups. Patients on score C had a higher risk of HT than the remaining groups (HT at 5 years: 1.3%, 6.6% and 36% for scores A, B and C, respectively; p<0.001). HT was associated with significantly lower OS (Cox-time dependent: HR 7.816, 95% CI 3.179-19.217; p<0.001). Conclusions: Herein we describe the everyday practice for diagnosis, stratification, and treatment of SMZL in Spain. Overall, 57% of the patients were managed according to the Guidelines. Our data support that Rituximab is the best treatment, when needed. Patients with score A who do not need immediate treatment after diagnosis and are followed with W&W policy have a very good outcome. In patients with scores A and B who were observed after initial diagnosis, the response to Rituximab at the time of need of therapy was not hampered when compared to patients receiving Rituximab immediately after diagnosis. HT is associated with reduced survival. The low number of cases in score C prevents us from drawing conclusions in this group at this time. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Evaluation of Epcoritamab and Rituximab Combination in Preclinical Models of B-Cell Non-Hodgkin's Lymphoma (NHL)

Background: Epcoritamab (Epco) is a CD3 bispecific antibody that induces selective, potent T-cell-mediated killing of CD20-positive malignant B-cells. In the phase 1/2 monotherapy study, subcutaneous administered Epco showed a favorable safety profile and promising efficacy, including complete responses in heavily pretreated patients with relapsed / refractory non-Hodgkin's lymphoma (Hutchings et al, Lancet 2021; Thieblemont et al, EHA 2022, LB2364; EPCORE NHL-1). Ongoing clinical studies combining Epco with standard-of-care therapies including combinations with Rituximab show promising preliminary anti-tumor activity in diffuse large B-cell lymphoma and follicular lymphoma (Falchi et al, ASCO 2022 abstracts 7523 and 7524; EPCORE NHL-2 arm 1 and 2; NCT04663347). Here we evaluated the competition for CD20 binding and functional interactions between these agents and modeled its impact on Epco, T-cell, and tumor cell trimer formation that drives Epco clinical activity. Aims: Investigate the preclinical binding and functional interaction between Epco and Rituximab to establish the potential for the combination of these agents in the treatment of B-cell NHL. Methods: Competition between Epco and Rituximab for binding to CD20 cells was assessed by Flow Cytometry after incubating the single labeled agent in the presence of increasing concentrations of the competitor and vice-versa (across 0.1 - 300 ug/ml evaluated for each agent), on a range of CD20 expressing lymphoma cell lines. Epco-induced-T cell activation and redirected T cell cytotoxicity was determined by co-culturing T cells with lymphoma cells with varying expression of CD20. Rituximab antibody-dependent cellular cytotoxicity (ADCC) activity was assessed by incubating fresh peripheral blood mononuclear cells with lymphoma cells in the presence of a CD3 control Epco antibody (DuoBody-ctrlxCD20). Data from binding and cytotoxicity was used to quantify the degree of binding curve shifts at different Rituximab:Epco concentrations as well as the impact on predicted trimer formation and cytotoxicity, based on modeling. Results: In binding assays, the addition of Rituximab resulted in a dose-dependent reduction of Epco binding to CD20 expressing lymphoma cell lines, with a significant reduction of Epco binding observed at clinically relevant Epco concentrations in cells with high CD20 expression levels (Figure 1). Similar binding interference interactions were observed for binding of Epco to cell lines with low and intermediate CD20 expression levels. Binding of Rituximab to cell lines expressing high CD20 levels was not significantly reduced by clinically relevant concentrations of Epco. In Epco functional studies, the addition of increasing concentrations of Rituximab did not affect Epco cytotoxic activity at clinically relevant range of Rituximab doses tested (Figure 2). Similarly, no effect of Rituximab on Epco-mediated T cell activation was observed at clinically relevant concentrations of Rituximab and Epco. ADCC activity at clinically relevant concentrations of Rituximab (10-250 ug/ml) was not impacted by incubation with the CD3 control Epco antibody (DuoBody-ctrlxCD20), even at concentrations exceeding the Epco clinical concentrations. Modeling and simulation of in vitro data showed that at clinically relevant concentration of Epco, the presence of clinically relevant concentration of Rituximab does not meaningfully impact Epco trimer formation, and the predicted trimer formation remains above EC90 relative to that needed for 50% cell kill. Conclusions: Our studies showed that while Rituximab exerts significant interference on Epco binding to CD20-expressing cells, tumor-cell cytotoxicity by Epco is minimally affected by clinically relevant concentrations of Rituximab. This conclusion is supported by preclinical modeling and simulations showing that Epco activity driven by trimer formation is not meaningfully impacted by clinical concentrations of Rituximab. Furthermore, we found a limited effect of Epco on Rituximab binding to CD20 and no impact on ADCC activity by Rituximab, thereby supporting potential synergy in the combination between these agents. Results from this study confirm the ability to combine Epco with CD20 antibodies, specifically with Rituximab, and the potential for synergistic activity of this combination. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal