Rituximab Combination Therapy Research Articles

Neutrophil-to-Lymphocyte Ratio as a Biomarker for Clinical Response After Autologous Hematopoietic Stem Cell Transplantation in Systemic Sclerosis.

Systemic sclerosis is a complex disease that affects various target organs, making it difficult to assess response and determine remission or relapse. A baseline Neutrophil-to-Lymphocyte Ratio (NLR) >2.95 is associated with severe progressive skin and lung disease and decreased 5-year survival in systemic sclerosis (SSc). However, it is unknown whether NLR changes in response to treatment. To retrospectively evaluate NLR changes as a biomarker for treatment response in SSc. Progressive diffuse SSc patients who were treated with autologous hematopoietic stem cell transplantation (AHSCT group), with combination therapy of rituximab and mycophenolate mofetil (combination group) or CAR-T cell therapy (CAR-T group) were recruited, along with healthy controls (HC group). NLR, modified Rodnan Skin Score (mRSS) and forced vital capacity (FVC)% predicted were repeatedly assessed over 2 years. Fifteen patients were recruited in the AHSCT group, 15 in the combination group, and six patients in the CAR-T group. Baseline mean NLR was high (>2.95) in AHSCT, combination groups, and CAR-T compared with HC. All treatment arms showed a statistically significant decrease in mRSS values and an increase in FVC% at each time point up to 12 months. In a linear mixed model, NLR significantly decreased up to 24 months only in the AHSCT group. NLR correlated with mRSS and FVC exclusively in the AHSCT group. NLR increased above 3 in two patients who experienced a relapse after AHSCT. NLR is a simple biomarker that correlated with outcome measures in SSc following AHSCT, but not with conventional therapy or CAR-T therapy. It is suggested that a decrease in NLR following AHSCT may indicate remission, whereas an increase may be associated with exacerbation. Further research is needed to validate these novel findings.

Combination therapy of dexamethasone, rituximab, and cyclosporine for adults with primary immune thrombocytopenia: a prospective observational study

ABSTRACT Background To assess the effectiveness of the combination of dexamethasone, rituximab, and cyclosporine in treating adults with primary immune thrombocytopenia (ITP). Research design and methods This prospective study enrolled consecutive adult patients diagnosed with ITP at the 967th Hospital of the Chinese People’s Liberation Army Joint Service Support Force Hospital between November 2019 and February 2023. Results Twenty-eight patients (13 males, median age 43.5 years) were included. All patients previously experienced ineffective or relapsed ITP, with a median disease duration of 26.5 (range, 7-72) months. At baseline, the median platelet (PLT) count was 13.5 × 109/L (8.25-20 × 109/L). Following treatment, the PLT counts were significantly increased at weeks 1, 3, and 4. The early response rates at weeks 1 and 4 were 82.1% (23/28 patients) and 71.4% (20/28 patients), respectively. The 1-, 3-, and 6-month response rates were 71.4% (20/28), 67.9% (19/28), and 75% (21/28). The treatment-free survival rates at 12 and 24 months were 82.35% (14/17) and 71.43% (10/14), respectively. Six patients experienced transient adverse reactions. Conclusions The combination of dexamethasone, rituximab, and cyclosporine may present a promising therapeutic option for patients with refractory ITP, with good tolerability and mild adverse reactions.

Treatment Resistant DPPX Antibody Associated Encephalitis With an Excellent Response to Combination Therapy of Rituximab and Monthly IVIG

Treatment Resistant DPPX Antibody Associated Encephalitis With an Excellent Response to Combination Therapy of Rituximab and Monthly IVIG

Retrospective study of the clinical manifestations and efficacy of immunotherapy for patients with acquired hemophilia A.

Raising awareness of acquired hemophilia A (AHA) and early diagnosis is critical to reduce the associated mortality rate. We aimed to characterize acquired hemophilia in Chinese patients and evaluate the effectiveness of immunotherapy. The clinical characteristics, laboratory test data, therapeutic approaches, and outcomes of 20 patients with AHA who were admitted to Xi'an Central Hospital between January 2012 and December 2020 were retrospectively studied. Nine of the patients (45%) were treated by single glucocorticoid administration; three (15%) with cyclophosphamide (CP) in combination with a glucocorticoid; four individuals (20%) received a combination therapy of rituximab with CP and glucocorticoid or rituximab with CP, vincristine, and a glucocorticoid; three (15%) by injection of human immunoglobulin in combination with a glucocorticoid; and one (5%) with CP alone. Six patients (30%) achieved total remission and 11 (55%) partial remission (PR), but three (15%) did not enter remission, indicating an objective response rate of 85%. Combination therapy with rituximab or intravenous human immunoglobulin achieves superior results in some patients with AHA. Immunosuppression and the administration of coagulation factors can rapidly control the disease and are efficacious, but >50% of patients only achieved PR. These findings suggest that the complete elimination of inhibitors requires prolonged immunosuppression therapy.

Effectiveness and safety of mycophenolate mofetil and rituximab combination therapy for immune idiopathic myopathies

IntroductionIdiopathic inflammatory myopathies (IIM) represent a rare and heterogenous group diseases, and their treatment is not fully defined yet. According to previous small case series, the combination of mycophenolate mofetil (MMF) and rituximab (RTX) may be effective in controlling difficult-to-treat patients. Our aim was to further explore the efficacy and safety of this combined approach in patients with IIM.MethodsPatients with IIM treated with the RTX/MMF combination in our Center were retrospectively identified. After the start of combination therapy, the efficacy was evaluated at 12 months (T12) according the 2016 ACR/EULAR response criteria for IIM. Cardiac imaging and pulmonary function tests were used to monitor disease activity in patients with myocarditis and interstitial lung disease, respectively. Adverse events were recorded over the follow-up period.ResultsAmong the 20 patients (median age 61 years; 70% female) included in the study, anti-synthetase syndrome was the most prevalent IIM subgroup (60%). At treatment start, muscle, heart, and lung were the most commonly actively affected organs. After 12 months, a moderate or major response was observed in all patients, and creatine kinase was significantly decreased (p-value = 0.012). Cardiac imaging and enzymes monitoring showed a reduction of heart inflammation, while pulmonary function tests improved in patients with lung involvement. No severe side effects were observed.ConclusionOur data show that combination of RTX and MMF is effective and safe in patients with severe and refractory IIM. Therefore, this combined treatment might represent a feasible approach for difficult-to-treat IIM cases.

Real-World Experience With Avacopan in Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis

Postmarketing data on outcomes of avacopan use in antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) are lacking. We performed a multicenter retrospective analysis of 92 patients with newly diagnosed or relapsing AAV who received therapy with avacopan. The coprimary outcome measures were clinical remission at 26 and 52 weeks. We use descriptive statistics and univariate logistic regression to assess outcomes and predictors of remission, respectively. Of the 92 patients, 23% (n = 21) had a baseline estimated glomerular filtration rate (eGFR)< 15 ml/min per 1.73 m2 and 10% on kidney replacement therapy at baseline. Among those with kidney involvement, mean (SD) enrollment eGFR was 33 (27) ml/min per 1.73 m2 with a mean (SD) change of+12 (25) and+20 (23) ml/min per 1.73 m2 at weeks 26 and 52, respectively. In addition to avacopan, 47% of patients received combination therapy of rituximab and low-dose cyclophosphamide, and 14% of patients received plasma exchange (PLEX). After induction, the median (interquartile range [IQR]) time to start avacopan was 3.6 (2.1-7.7) weeks, and the median time to discontinue prednisone after starting avacopan was 5.6 (3.3-9.5) weeks. Clinical remission was achieved in 90% of patients at week 26 and 84% of patients at week 52. Of the patients, 20% stopped avacopan due to adverse events, with the most common being elevated serum aminotransferases (4.3%). A high rate of remission and an acceptable safety profile were observed with the use of avacopan in the treatment of AAV in this postmarketing analysis, including the populations excluded from the ADVOCATE trial.

Thrombopoietin receptor agonist and rituximab combination therapy in patients with refractory primary immune thrombocytopenia.

The aim of our study was to evaluate the efficacy of this therapy in patients with refractory primary immune thrombocytopenia. It is crucial to develop alternative treatment methods for this patient group in order to achieve better response. This combination therapy combines two different mechanisms of action, which is promising in terms of targeting pathophysiology of immune thrombocytopenia. We conducted a retrospective study, which included all patients who were diagnosed with refractory primary immune thrombocytopenia and received TPO-RA and rituximab at the General Hematology Department, Copernicus Memorial Hospital in Lodz, Poland. We assessed the response, time to response and treatment-free remission (TFR). After 1 month of treatment, the complete response (CR1, PLT >100 g/l) was achieved in 62.5% patients, and response (R1, PLT >30 g/l) was achieved in 62.5% patients. The median PLT was 175 × 10 9 /l. Within 1 month of treatment, 87.5% of patients achieved TFR. Adequately, after 6 months, CR6 and R6 was 62.5 and 75%. The median PLT was 182 × 10 9 /l. Treatment-free remission 6 months after completion was in 50% of patients. The study group achieved response to treatment, which suggests that combination of TPO-RA and rituximab is effective and relatively well tolerated. Prospective study on larger group of patients is needed to better evaluate the efficiency and safety of this treatment.

Secondary central nervous system involvement in patients with diffuse large B-cell lymphoma treated with rituximab combined CHOP therapy – a supplementary analysis of JCOG0601

Secondary central nervous system involvement (sCNSi) in diffuse large B-cell lymphoma (DLBCL) is fatal. However, its features in patients with sCNSi who are categorized as lower risk by international prognostic index (IPI) or CNS-IPI are not yet fully understood. In the present analysis, we evaluated DLBCL patients who developed sCNSi at their first progression and who participated in JCOG0601, most of whom were lower risk by IPI. Of 409 patients, 21 (5.1%) developed sCNSi during a median follow-up of 4.9 years. Five-year cumulative incidence of sCNSi were 5.1%; and 4.0%, 5.3%, and 11.5% at low, intermediate, and high risk of CNS-IPI, respectively. The most common locations of extranodal lesions at the time of registration in patients with sCNSi were the stomach (n = 4), paranasal cavity (n = 3), and bone marrow (n = 2). In univariable analysis, paranasal cavity lesion was a high-risk factor for sCNSi (subdistribution hazard ratio, 4.34 [95% confidence interval 1.28–14.73]). Median overall survival after sCNSi was 1.3 years, with a 2-year overall survival rate of 39.3%. The incidence of sCNSi in DLBCL patients at lower risk of CNS-IPI was low, as previously reported, but paranasal cavity lesion might indicate high risk for organ involvement.Clinical trial registrationJCOG0601 was registered in the UMIN Clinical Trials Registry (UMIN000000929, date of registration; December 04, 2007) and the Japan Registry of Clinical Trials (jRCTs031180139, date of registration; February 20, 2019).

Acrue: A Phase 2, Open-Label Study of Acalabrutinib in Combination with Rituximab in Elderly and/or Frail Patients with Treatment-Naive Diffuse Large B-Cell Lymphoma

Background and Significance: Patients aged ≥80 years with diffuse large B-cell lymphoma (DLBCL) account for approximately 18% of DLBCL cases in the United States (Morrison et al. Future Oncol. 2018). Standard-of-care chemoimmunotherapy (CIT) regimens such as rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP), including reduced doses of CHOP (R-miniCHOP), are not well tolerated in elderly and/or frail patients, leading to high treatment-related mortality rates (Boslooper et al. Leuk Lymphoma. 2014; Freudenberger et al. Ann Hematol. 2021; Peyrade et al. Lancet Oncol. 2011). Therefore, safe, effective, and convenient treatment alternatives to CIT are needed. Acalabrutinib is a highly selective, second-generation Bruton tyrosine kinase inhibitor approved for the treatment of patients with relapsed/refractory mantle cell lymphoma and in patients with chronic lymphocytic leukemia. Acalabrutinib monotherapy has demonstrated encouraging activity in patients with DLBCL in phase 1b (NCT02112526) and phase 2 (NCT04002947) studies (Strati et al. Haematologica. 2021; Roschewski et al. Blood. 2021). However, neither of these studies were conducted specifically in a population of elderly and/or frail patients. Study Design and Methods: ACRUE (NCT05952024) is a phase 2, open-label, single-arm, global, multicenter study of acalabrutinib plus rituximab in elderly and/or frail patients with treatment-naive (TN) DLBCL who are unable to tolerate standard CIT ( Figure). Eligible patients are aged ≥80 years or aged 65-79 years with impairment in ≥1 activity of daily living (ADL) or instrumental ADL (IADL), or with cardiac/renal/liver function impairment or other comorbidities that render them unable to tolerate CIT. Furthermore, patients must have histologically confirmed CD20-positiveDLBCL (not otherwise specified), according to WHO 2016 classification, an Ann Arbor classification of stage II, III, or IV disease, an Eastern Cooperative Oncology Group performance status of 0-2, and ≥1 measurable lesion. Patients with active central nervous system involvement by lymphoma, leptomeningeal disease, or spinal cord compression, or significant cardiovascular disease within 6 months of screening are excluded. Target enrollment is 80 patients. Patients will receive acalabrutinib plus rituximab combination for 8 cycles (acalabrutinib 100 mg orally twice daily beginning on day 1 of cycles 1-8; rituximab 375 mg/m 2 intravenously on C1D15, then 1400 mg subcutaneously, on day 1 of cycles 2-8; cycles 1-8 are 21 days/cycle), followed by acalabrutinib monotherapy until disease progression, unacceptable toxicity, or 24 months (cycles 9-28 are 28 days/cycle). The primary endpoint is the percentage of patients with grade 3-4 treatment-emergent adverse events. The key secondary endpoint is investigator-assessed objective response rate per Lugano 2014 criteria. Other secondary endpoints include progression-free survival, event-free survival, overall survival, duration of response, and Timed Up and Go test. Exploratory biomarker analyses may include genomic characterization of baseline samples to evaluate predictors of survival, and of progression samples to evaluate genomic resistance mechanisms. Descriptive safety and efficacy data will be summarized. If patients discontinue treatment prior to completing 28 cycles of therapy, they will be followed every 12 weeks after their last treatment dose for up to 2 years. Patients who are still on treatment at the end of the study and are deriving clinical benefit may receive continued treatment, with assessments reverting to standard of care. Enrollment is planned to begin Q4 of 2023 in approximately 40 sites from North and South America and Asia. Summary: This study will help determine if acalabrutinib plus rituximab combination therapy is tolerable and effective in elderly and/or frail patients with TN DLBCL who are unable to tolerate CIT.

Zanubrutinib, Polatuzumab Vedotin and Rituximab (ZPR) Combination Regimen for Relapsed/Refractory Patients with Diffuse Large B-Cell Lymphoma

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous and invasive lymphoma. About 30% of patients are difficult to cure or relapse after R-CHOP treatment, known as relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). Patients who are not suitable for high-dose chemotherapy followed by autologous stem cell rescue, rely more on the discovery of new drugs and proposals of new treatment plans. Polatuzumab vedotin (Pola) is an antibody-drug conjugate that targets the B-cell antigen CD79b and delivers monomethyl auristatin E (MMAE). It is recently available in China and approved in combination with Bendamustine and Rituximab for r/r DLBCL. However, real-world data on Pola-based regimens are limited. Here, we propose ZPR (combination of Zanubrutinib, Polatuzumab vedotin and Rituximab) as a potential salvage treatment in r/r DLBCL patients, aiming to explore its efficacy and safety in our single center. Response characteristics in patients received ZPR therapy There were already eight r/r DLBCL patients treated with ZPR regimen at our institution between April 1 and July 31, 2023. Informed consent and biological sample donation informed consent were both signed by each participant. Patients were 69 years old on median and half of them were non-GCB type. Seven patients are classified as stage IV. The median number of treatment lines is two. Patients were given Zanubrutinib 160mg bid daily; Polatuzumab vedotin 1.8 mg/kg and Rituximab 375 mg/m 2 on the first day of each cycle (every 21 days per cycle). Four patients completed 3 cycles of ZPR and three underwent a mid-term evaluation. Results showed that the complete remission (CR) rate was 100% (Figure 1). In terms of adverse events, hematological toxicity grade is not greater than level 2 of Common Terminology Criteria for Adverse Events (CTCAE). One patient developed a pulmonary infection during the treatment. The Rationale for the combination of Polatuzumab vedotin, Rituximab and Zanubrutinib The combination therapy of bruton's tyrosine kinase inhibitor (BTKi) with anti-CD20 therapy has been used in many B-cell lymphomas. It was proposed that combining these two drugs will target and clear blood lymphocytes and shorten the time to respond in chronic lymphocytic leukemia patients. Compared with the first generation BTKi the new generation BTKi Zanubrutinib has a higher selectivity and fewer off-target effects on BTK. Meanwhile, Natsumi Kawasaki et al discovered that Pola increased the expression of CD20 and sensitized Pola refractory cells to Rituximab-induced complement-dependent cytotoxicity (CDC). While the release of MMAE, a chemical component of Pola, results in microtubule disruption and cycle arrest. These findings provide a scientific rationale for employing the Pola-Rituximab combination therapy to treat DLBCL patients. However, the combination of Pola and Zanubrutinib does not show a clear mutual antagonism effect. The molecular rationale for the combination of these two drugs needs further exploration. Who are suitable for ZPR regimen? Patients who are diagnosed with r/r DLBCL after standard first-line treatment failure: ECOG≥2Age≥70As a bridging therapy for patients waiting for ASCT or CAR-T therapyAge＜70 expect a high quality of life, still need working, or going to schoolUnable to tolerate standard-dose of chemotherapy due to hematological toxicity (need a blood transfusion, treatment delay, or dosage reduction) Prospective study to be continued Due to the good response of our three r/r DLBCL patients, we intended to conduct a “Prospective single-arm, single-center clinical study of Zanubrutinib, Polatuzumab vedotin and Rituximab (ZPR) regimen in relapsed/refractory patients with diffuse large B-cell lymphoma” to learn more about the impact of the ZPR regimen in the treatment of r/r DLBCL. We got the approval from the Investigator-Initiated Trial (IIT) Scientific Review Board of Zhongshan Hospital after discussing the risks and benefits of ZPR regimen with them. This protocol has also been reviewed and approved by the Institutional Review Board (IRB) of Zhongshan Hospital Affiliated to Fudan University (B2023-186R) and will follow the principles of the Helsinki Declaration. The protocol was previously registered on ClinicalTrials. gov (NCT05940051) . We illustrated the flowchart of our study in Figure 2.

First-in-Human Dose-Escalation and -Expansion Trial with Sirpα Antibody BYON4228 in R/R B-Cell NHL

Introduction: Blocking of the immune checkpoint CD47-SIRPα promotes myeloid cell-mediated innate as well as adaptive immunity towards tumor cells. Antibodies in development are either directed against CD47 or SIRPα and in combination with tumor-targeting antibodies, checkpoint inhibitors, chemotherapeutics or other agents. The humanized SIRPα antibody BYON4228 (van Helden et al (2023) JITC 11: e006567) has been designed with three distinguishing characteristics compared to other CD47- or SIRPα-directed therapies which makes BYON4228 potentially best-in-class: 1.High specificity for SIRPα and no binding to SIRPγ on T cells which enables maximal contribution of T cells and therefore maximal anti-tumor immune response; 2.Silenced Fc backbone (IgG1-L234A/L235) which potentially results in reduced toxicity as confirmed in nonclinical studies showing no anemia or neutropenia in monkey; 3.Binding to both allelic forms of SIRPα (α 1 and α BIT) covering a broad patient population. Phase 1 clinical trial design: BYON4228.001 (NCT05737628) is the first-in-human clinical trial of BYON4228, in combination with rituximab, in relapsed or refractory (R/R) B-cell Non-Hodgkin's lymphoma (NHL). Part 1 (dose escalation) evaluates the safety, tolerability and Pharmacokinetics (PK) of, and receptor occupancy by BYON4228 to determine the maximum tolerated dose (MTD) or optimal biological dose (OBD) if the MTD is not reached, and recommended dose for expansion (RDE). A 28-day flat dose escalation schedule starting at 7 mg will be followed in a standard 3+3 design. Notably, only 1 cycle BYON4228 monotherapy will be given in each patient before combining with rituximab (375 mg/m 2 first cycle weekly administration; thereafter every 4 weeks for a total of 6 cycles). In part 2 (cohort expansion) BYON4228 + rituximab combination therapy will be given from cycle 1 onwards to further evaluate safety and efficacy in up to 24 additional diffuse large B cell lymphoma (DLBCL) patients and up to 24 patients with either marginal zone lymphoma (MZL) or follicular lymphoma (FL). This trial design of only 1 cycle monotherapy and swiftly moving into combination therapy not only allows to investigate PK and safety of BYON4228 but also efficacy of combination treatment with rituximab in a relevant therapeutic setting. Enrollment is ongoing in The Netherlands, United Kingdom, Italy and Spain since June 2023. Key inclusion criteria include, for part 1: B-cell NHL expressing CD20 by immunohistochemistry (IHC) or flow cytometry, R/R to at least 2 prior lines of therapy; for part 2, cohort A: Histologically confirmed DLBCL expressing CD20 R/R to front-line therapy, or second-line salvage regimens; for part 2, cohort B: Histologically confirmed MZL or FL (Grade 1-3a) expressing CD20, R/R to at least 2 prior lines of therapy. Autologous or allogeneic hematopoietic cell transplantation and autologous CAR-T cell therapy are allowed as prior lines. Key exclusion criteria include prior treatment with CD47- or SIRPα- targeting agents at any time; other anticancer therapy including investigational agents within 2 weeks or within at least 4 times the elimination half-life; Burkitt's lymphoma; history of active auto-immune disorders, active infections or uncontrolled systemic disease. Tumor response is determined according to Lugano and LYRIC criteria. An extensive biomarker program in the peripheral blood and bone marrow is included in the trial.

Cost-effectiveness of combination therapy of polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisolone for previously untreated diffuse large B-cell lymphoma in Japan

AimThe POLARIX trial showed that Pola + R-CHP (polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisolone) prolongs progression-free survival (PFS) in patients with previously untreated diffuse large B-cell lymphoma (DLBCL) compared with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone), the conventional standard of care, with a similar safety profile. However, Pola + R-CHP has not been evaluated from the viewpoint of health economics in Japan. This study evaluates the cost-effectiveness of Pola + R-CHP for previously untreated DLBCL from a Japanese public healthcare payer’s perspective.MethodsA partitioned survival analysis model was constructed to estimate lifetime costs and effectiveness of Pola + R-CHP and R-CHOP in previously untreated DLBCL who had an International Prognostic Index score (IPI) score of ≥2. A parametric survival model was applied to data analyzed in the POLARIX trial to estimate the lifetime overall survival (OS) and PFS for each treatment. The parameters required for the model were based on the results of a literature search and expert opinion.ResultsThe incremental cost-effectiveness ratio (ICER) of Pola + R-CHP vs. R-CHOP was JPY2,710,238 per quality-adjusted life year (QALY), less than the ICER of JPY7.5 million per QALY that is considered to be cost-effective based on the threshold of the Japanese cost-effectiveness evaluation system. One-way sensitivity analysis showed that the parameters influencing the results of the analysis were median PFS and the total cost per regimen of salvage chemotherapy, patient weight, and patient age. Probabilistic sensitivity analysis showed that the probability of Pola + R-CHP having superior cost-effectiveness was 99.2% when the reference value was JPY7.5 million. The results of scenario analysis suggested that prolongation of PFS was an important factor in the evaluation of cost-effectiveness in previously untreated DLBCL with or without prolongation of OS.ConclusionsThis study suggests that Pola + R-CHP is a cost-effective treatment for previously untreated DLBCL in Japan under the public health insurance system.

Evaluating the effectiveness and tolerability of chemotherapy in hairy cell leukemia: A comprehensive systematic review and meta-analysis.

e19547 Background: Hairy cell leukaemia (HCL) is a rare, chronic B cell cancer that involves the bone marrow, peripheral blood, and spleen. Many treatment options are available for HCL. Our study aims to elucidate the safety and efficacy of each intervention through the pooled proportion of response to treatment and adverse events. Methods: We conducted a literature search across PubMed, Embase, Cochrane, and Google Scholar from inception till February 2023. We included clinical trials and cohorts of patients with HCL receiving modern anticancer drugs (cladribine, rituximab, cladribine plus rituximab, BRAF inhibitors, anti-CD22 monoclonal antibodies, and ibrutinib). The primary efficacy outcomes were Objective Response Rate (ORR) and Complete Response Rate (CRR) and the primary safety outcome was adverse effects (AEs). We used OpenMetaAnalyst to pool data using the Hedges-Olkin Random Effects Model, with subgroup analysis for HCL type and study design. Results: Our meta-analysis included 44 studies (28 trials and 16 cohorts) with 3976 patients with HCL. The median age was 56.7 years. The highest efficacy was seen in patients receiving combination therapy of cladribine and rituximab, with an ORR of 97% and CRR of 92%. Cladribine monotherapy showed an ORR of 95% and CRR of 79%, while rituximab monotherapy had an ORR of 62% and CRR of 31%. BRAF inhibitors, anti-CD22 monoclonal antibodies, and ibrutinib showed less efficacy, with ORRs of 92%,78% and 51% and CRRs of 41%, 49%, and 17% respectively. Subgroup analysis for study design and HCL type did not resolve heterogeneity. The ORR and CRR with 95% Confidence Intervals and AEs for each regimen are given in the table. Conclusions: Cladribine with rituximab is the most effective treatment for untreated and relapsed HCL patients, with neutropenia as the most common AE. Since we pooled the proportions for treatment-naïve and relapsed cases together due to inavailability of segregated data, the results should be used cautiously in clinical decision making and limit the derivation of consensus for treatment of newly diagnosed or relapsed HCL. [Table: see text]

Comparison of high-dose IVIG and rituximab versus rituximab as a preemptive therapy for de novo donor-specific antibodies in kidney transplant patients

De novo donor-specific antibody (dnDSA) is associated with a higher risk of kidney graft failure. However, it is unknown whether preemptive treatment of subclinical dnDSA is beneficial. Here, we assessed the efficacy of high-dose intravenous immunoglobulin (IVIG) and rituximab combination therapy for subclinical dnDSA. An open-label randomized controlled clinical trial was conducted at two Korean institutions. Adult (aged ≥ 19 years) kidney transplant patients with subclinical class II dnDSA (mean fluorescence intensity ≥ 1000) were enrolled. Eligible participants were randomly assigned to receive rituximab or rituximab with IVIG at a 1:1 ratio. The primary endpoint was the change in dnDSA titer at 3 and 12 months after treatment. A total of 46 patients (24 for rituximab and 22 for rituximab with IVIG) were included in the analysis. The mean baseline estimated glomerular filtration rate was 66.7 ± 16.3 mL/min/1.73 m2. The titer decline of immune-dominant dnDSA at 12 months in both the preemptive groups was significant. However, there was no difference between the two groups at 12 months. Either kidney allograft function or proteinuria did not differ between the two groups. No antibody-mediated rejection occurred in either group. Preemptive treatment with high-dose IVIG combined with rituximab did not show a better dnDSA reduction compared with rituximab alone.Trial registration: IVIG/Rituximab versus Rituximab in Kidney Transplant With de Novo Donor-specific Antibodies (ClinicalTrials.gov Identifier: NCT04033276, first trial registration (26/07/2019).

OA25 Identification of biomarkers to stratify response to combination therapy with belimumab and rituximab in a randomized trial, BEAT-LUPUS for systemic lupus erythematosus

Abstract Background/Aims The BEAT-lupus double-blind randomised trial demonstrated that belimumab (anti-BAFF antibody) reduced the number of severe-flares (compared to placebo) after B-cell depletion (rituximab) in patients with systemic lupus erythematosus (SLE)(1). We longitudinally immune profiled patients recruited to the trial to identify which patients would benefit most from belimumab after rituximab combination therapy. Methods We constructed two models (because the number of patients who provided serum/blood RNA samples and peripheral blood mononuclear cells differed) using baseline data to predict a major clinical response (MCR)(2) to belimumab after rituximab at 52-weeks utilising conventional and machine learning approaches: A) Model 1: serum autoantibodies and cytokines, peripheral blood RNA expression, clinical data, and routinely collected laboratory-markers (10 responders, 11 non-responders). B) Model 2: B-cell flow-cytometry (8 responders, 8 non-responders). The emerging key variables were then used as effect modifiers comparing response to belimumab and placebo after rituximab. Results Baseline serum IgA2 anti-dsDNA antibody levels emerged from model 1 as the key predictor of MCR with an AUROC (area under the curve of the receiver operator characteristic) of 0.81 (95% CI: 0.70-0.96) in predicting an MCR by 52-weeks in the belimumab arm. An optimal cut point of serum IgA2 anti-dsDNA antibody (10.7 AU/arbitrary unit), derived from AUROC, was applied as an effect modifier which improved the delta between response to belimumab vs placebo from 13% (without the effect modifier) to 48% (95% CI: 10-70; p = 0.021) (Belimumab - 64% [9 responders, 5 non-responders], placebo - 16% [2 responders, 10 non-responders]). Belimumab significantly reduced serum IgA2 anti-dsDNA antibody levels compared to placebo at 52-weeks (difference: 20 AU; 95% CI: 13-27; p &amp;lt; 0.001) only in those patients who achieved an MCR, falling by 60% from baseline (difference: 23 AU; 95% CI: 11-35; p &amp;lt; 0.001, compared to non-response). Prediction model 2 identified the frequency of T-bet+CD11c+DNM-2 (double negative memory B-cell, type-2: CD11c+T-bet+CD38-CD27-IgD-CD21-CD24-) as the strongest predictor of MCR by 52-weeks in the belimumab arm with an AUROC of 1.00 (95% CI: 1.00-1.00). Using T-bet+CD11c+DNM-2 as an effect modifier (optimal cut point: 14.2% of total B-cells) the delta improved from 13% to 71% (95% CI: 23-92; p = 0.007) (Belimumab - 100% [8 responders, 0 non-responders], placebo - 29% [2 responders, 5 non-responders]). The frequency of T-bet+CD11c+DNM-2 was significantly lower in the belimumab arm at 52-weeks compared to placebo (difference: 6%; 95% CI: 3-11; p = 0.001), and dropped by 48% from baseline in belimumab responders (difference with non-responders: 11%; 95% CI: 6-15; p &amp;lt; 0.001). Conclusion High baseline serum IgA2 anti-dsDNA antibody and peripheral blood T-bet+CD11c+DNM-2 B-cell frequency could guide patient selection for belimumab after rituximab combination therapy thereby improving outcomes and access to targeted therapies for patients with SLE. Exploration of the underlying mechanisms and confirmation of these results including combining the two prediction models in a larger clinical trial are required. Reference 1. Shipa M, et al. Annals of Internal Medicine. 2021;174:1647-57. 2. McDonald S, et al. Lupus Sci Med. 2022;9:e000584. Disclosure M. Shipa: Grants/research support; Versus arthritis, LUPUS-UK. M. Parvaz: None. D. Nguyen: None. L. Santos: None. D.A. Isenberg: Consultancies; Astra Zeneca, Eli Lilly, Merck Serono, Servier and UCB. C. Gordon: Consultancies; Center for Disease Control and Prevention, AbbVie, Amgen, Astra-Zeneca, EMD Serono, MGP, Sanofi and UCB. M.R. Ehrenstein: Consultancies; GSK. Grants/research support; Versus arthritis.

Landscape of BCL2 Resistance Mutations in a Real-World Cohort of Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia Treated with Venetoclax

The oral, highly selective Bcl2 inhibitor venetoclax has substantially improved the therapeutic landscape of chronic lymphocytic leukemia (CLL). Despite the remarkable response rates in patients with relapsed/refractory (R/R) disease, acquired resistance is the leading cause of treatment failure, with somatic BCL2 mutations being the predominant genetic drivers underpinning venetoclax resistance. To assess the correlation between disease progression and the most common BCL2 mutations G101V and D103Y, sensitive (10-4) screening for the most common BCL2 mutations G101V and D103Y was performed in 67 R/R CLL patients during venetoclax single-agent or venetoclax-rituximab combination therapy. With a median follow-up time of 23 months, BCL2 G101V and D103Y were detected in 10.4% (7/67) and 11.9% (8/67) of the cases, respectively, with four patients harboring both resistance mutations. Ten out of eleven patients carrying BCL2 G101V and/or D103Y experienced relapse during the follow-up period, representing 43.5% of the cases (10/23) showing clinical signs of disease progression. All BCL2 G101V or D103Y variants were detected in patients receiving venetoclax as a continuous single-agent treatment while these mutations were not observed during or after fixed-duration venetoclax therapy. Targeted ultra-deep sequencing of BCL2 uncovered three additional variants in four patient samples obtained at relapse, suggesting convergent evolution and implying a cooperating role of BCL2 mutations in driving venetoclax resistance. This cohort is the largest R/R CLL patient population reported to date in which BCL2 resistance mutations were investigated. Our study demonstrates the feasibility and clinical value of sensitive screening for BCL2 resistance mutations in R/R CLL.

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.

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

S2063 Mantle Cell Lymphoma Presenting as Multiple Lymphomatous Polyposis of the Colon

Introduction: Mantle Cell Lymphoma (MCL), a type of non-Hodgkin lymphoma (NHL) is an aggressive neoplasm affecting the lymphatic system. Its incidence is 1–2 cases/105 people/year and accounts for only 5-6% of all cases of NHL. Multiple lymphomatous polyposis (MLP) is a rare presentation seen in MCL consisting of diffuse nodules or polyps covering multiple sites of the gastrointestinal tract. Case Description/Methods: A 68-year-old female with a past medical history of hypertension presented to the clinic with a one-year history of mild diffuse abdominal pain, change in bowel habits including loose stools, and significant involuntary weight loss. A review of systems, physical examination, and routine blood work was non-remarkable. The upper endoscopy was normal but a colonoscopy revealed numerous 1-10 mm submucosal nodules in the entire colon. Biopsies obtained from the nodules of the colon revealed colonic mucosa infiltrated with monotonous, small to medium-sized lymphocytes with irregular nuclear contour, and scant cytoplasm. Immunohistochemistry and immunophenotypic analysis were positive for CD20, CD5, Cyclin D1, BCL6, BCL 2, SOX 11, and negative for CD 10, and P 53. FISH testing revealed 11,14 translocations, consistent with Mantle Cell Lymphoma. CT scan of the abdomen showed pre-carinal, right hilar, extensive para-aortic, and mesenteric lymphadenopathy consistent with stage 4 Mantle Cell Lymphoma. She was subsequently started on Bendamustine and Rituximab combination therapy followed by Rituximab for maintenance. There was a significant improvement in her clinical status with progressive weight recovery. Follow-up upper and lower endoscopic examinations after 6 cycles revealed complete remission with the absence of all polypoid lesions in the GI tract (Figure 1). Discussion: The initial presentation of MCL can widely vary from being asymptomatic to having systemic symptoms of fever and weight loss to marked lymphadenopathy on physical examination. Although 15-30% of individuals with Mantle cell lymphoma (MCL) are reported with involvement in the gastrointestinal (GI) tract, MLP is seen only in less than 10%. It is important for clinicians to not only incorporate MCL as a differential in their workup when they come across diffuse polyps in the GI tract but also to differentiate it from other similar disease processes that present with multiple polyps in the colon. A definitive diagnosis of MLP requires biopsy and histological examination of the tissue with immunophenotypic and immunohistochemistry analysis.Figure 1.: Multiple sessile polypoid lesions of different sizes throughout the colon.

Successful Treatment of Recalcitrant Juvenile Pemphigus Foliaceus with Intravenous Immunoglobulin and Rituximab

Pemphigus foliaceus (PF) is uncommon among children. The usage of rituximab in childhood PF is even less documented. We reported a case of a 16-year-old boy with juvenile PF who failed conventional treatments and was started on combination therapy of intravenous immunoglobulin (IVIG) and rituximab followed by six-monthly rituximab maintenance therapy. He achieved full remission and no adverse effects. Therefore, in cases of recalcitrant juvenile PF, combination therapy of IVIG and rituximab can be considered.