Rituximab Maintenance Therapy Research Articles

#2154 Rituximab in the treatment of PLA2R-associated membranous nephropathy: insights from a hospital centre experience

Abstract Background and Aims Rituximab (RTX) is recommended as the first-line therapy for PLA2R-associated Membranous Nephropathy in patients with a moderate to high risk of progressive loss of kidney function, according to the KDIGO 2021 guidelines. This recommendation is based on the superior long-term efficacy and improved safety profile of RTX. This study aims to assess the use of RTX for the treatment of for PLA2R-associated Membranous Nephropathy at a hospital centre. Method A retrospective study was conducted on patients diagnosed with PLA2R-associated Membranous Nephropathy who underwent their first RTX administration between 2017 and 2022 at a tertiary hospital centre. Exclusion criteria involved patients with less than 6 months of follow-up post-RTX. The study evaluated the occurrence of immune remission, clinical remission, as well as instances of immune and proteinuria relapse, and recorded any adverse events. Results A total of 11 patients were included, with 54.5% being male. The mean age was 60.4 ± 14.7 years, and the median disease duration 69.0 [8.0-87.0] months. The mean follow-up time post-RTX was 36.7 ± 23.3 months. Regarding the risk of progressive loss of kidney function, 8 patients were classified as high risk, 1 as moderate risk, and 2 as low risk. RTX served as the initial immunosuppressive therapy for only 3 patients. Additional immunosuppressive therapies post-RTX, including further RTX doses, were administrated in 63.6% (n = 7) of patients. No response was observed in 18.2% (n = 2). Immune remission was achieved in 81.8% (n = 9), mean time of 3.8 ± 1.4 months. Within this group 55.5% (n = 5) patients achieved complete remission, 22.2% (n = 2) experienced partial remission, and 22.2% (n = 2) maintained nephrotic proteinuria, with immune remission consistently preceding clinical remission. Relapses occurred in 45.5% (n = 5), at a mean time of 20.8 ± 13.5 months. Patients with lower serum albumin at time of RTX administration were more likely to experience non-response or relapse (T (9) = 2.51, p = 0.03), with a Youden Index cut-off of 3.2 g/dL, demonstrating a sensitivity of 100% and a specificity of 85.7%. Patients with anti-PLA2R exceeding 150 RU/mL exhibited no response or relapsed. Four patients (36.4%) remained free of relapses throughout the entire follow-up period, mean time of 22.8 ± 10.0 months, with 1 keeping RTX maintenance therapy. During the 6 months post-RTX, 36.4% (n = 4) of patients experienced adverse events. Conclusion Rituximab demonstrated both efficacy and safety in treating PLA2R-associated Membranous Nephropathy. However, lower serum albumin levels and anti-PLA2R > 150 RU/mL at time of RTX administration were associated with worse response. Given the substantial need for additional immunosuppression, and considering lower albumin values and higher anti-PLA2R titres as risk markers, it is recommended to closely monitor these patients. Anti-PLA2R titres showed a meaningful association with disease activity, preceding changes in proteinuria levels. Therefore, tracking disease progression through the measurement of anti-PLA2R titres not only guides clinical decisions but also enables a judicious approach to subsequent RTX administrations.

Rituximab in the Treatment of LRP4-Antibody-Positive Myasthenia Gravis: A Case Report

Antibodies against LRP4 were found in 2-4% of patients with myasthenia gravis (MG). LRP4-antibody-positive (LRP4+) MG presents with more severe disease with bulbar involvement. No standard treatment guideline has been established for this subtype. We identified a LRP4+MG patient with severe symptoms including bulbar dysfunction that were refractory to standard therapy. Rituximab was started due to treatment failure with standard therapy. At the time of initiation of rituximab, patient was on plasmapheresis every 1-2 weeks. Her work and quality of life were greatly compromised. Six weeks after initiating rituximab therapy, remarkable improvements in dyspnea, dysphagia, ptosis, and proximal limb muscle strength were reported without adverse events. Improvements in 3 standardized Myasthenia Gravis scoring systems were observed. The maintenance plasmapheresis was discontinued and pyridostigmine dose decreased by 50% because of sufficient symptom control. Stable improvement was achieved with rituximab maintenance therapy spaced 5 months apart. Our case demonstrates rapid onset of efficacy of rituximab in patient with refractory LRP4+MG. This response and the proposed mechanism of action of LPR4-Ab suggest that the efficacy of rituximab in LRP4+MG may parallel that in MuSK+MG. Further exploration of this treatment option is warranted.

Comparing R-Bendamustine vs. R-CHOP Plus Maintenance Therapy as First-Line Systemic Treatment in Follicular Lymphoma: A Multicenter Retrospective GELTAMO Study.

Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and R-bendamustine (R-B) are the most common frontline treatment strategies for advanced-stage follicular lymphoma (FL). After R-CHOP induction therapy, using rituximab for maintenance therapy notably improves outcomes; however, whether this can be achieved by using the same approach after R-B therapy is still being determined. This retrospective analysis compared 476 FL patients from 17 GELTAMO centers who received R-based regimens followed by rituximab maintenance therapy for untreated advanced-stage FL. The complete response rate at the end of induction was higher with R-B and relapses were more frequent with R-CHOP. During induction, cytopenias were significantly more frequent with R-CHOP and so was the use of colony-stimulating factors. During maintenance therapy, R-B showed more neutropenia and infectious toxicity. After a median follow-up of 81 months (95% CI: 77-86), the 6-year rates of progression-free survival (PFS) were 79% (95% CI: 72-86) for R-bendamustine vs. 67% (95% CI: 61-73) for R-CHOP (p = 0.046), and 6-year overall survival (OS) values were 91% (95% CI: 86-96) for R-B vs. 91% (95% CI: 87-94) for R-CHOP (p = 0.49). In conclusion, R-B followed by rituximab maintenance therapy in patients with previously untreated FL resulted in significantly longer PFS than R-CHOP, with older patients also benefiting from this treatment without further toxicity. Adverse events during maintenance were more frequent with R-B without impacting mortality.

Фолликулярная лимфома 1–3А цитологического типа с наличием или отсутствием t(14;18)(q32;q21): прогноз, выбор противоопухолевой терапии и ее результаты

Aim. To determine the prognostic value of t(14;18)(q32;q21) in follicular lymphoma (FL) of grades 1–3А, to assess the chemotherapy efficacy in “t(14;18)+ FL” and “t(14;18)– FL” patients, and to analyze the cases of ineffective therapy.
 Materials & Methods. The retrospective/prospective study carried out at the National Research Center for Hematology in the period of 2001–2022 enrolled 362 patients with newly diagnosed FL of grades 1–3А. Their risk stratification was based on predictive models FLIPI and PPI3 (Personalized Predictive Index[1]). The patients were 30–81 years of age (median 52 years). There were 225 women and 137 men. They received the following regimens: R-B (n = 80), R-CHOP (n = 189), R-CHOP (4 cycles) + R-DHAP (2 cycles) (n = 28), and R-CHOP (4 cycles) + R-DHAP (2 cycles) + auto-HSCT in the first-line therapy (n = 65). For 2 years, maintenance rituximab therapy was administered to all the enrolled patients, whichever drug chemotherapy they received. Standard cytogenetic analysis and FISH were carried out in 265/362 (73 %) patients.
 Results. Patients were divided into two comparable groups: “t(14;18)+ FL” (n = 196) and “t(14;18)– FL” (n = 69). Patients without cytogenetics/FISH (n = 97) were excluded from the analysis. In patients without t(14;18), poor prognostic factors, such as grade 3А (p = 0.003) and Ki-67 > 35 % (p = 0.001), were identified significantly more often, and also high PPI3 risk was reported (p = 0.008). No differences (p = 0.84) were detected during FLIPI risk stratification of patients. Bone marrow lesions were observed significantly more often in “t(14;18)+ FL” compared to “t(14;18)– FL” (p = 0.002). The chemotherapy outcomes, such as 2-year EFS and OS, appeared to be considerably worse in “t(14;18)– FL” compared to “t(14;18)+ FL” patients.
 Conclusion. The group of FL patients with t(14;18) appeared to be most numerous and more prognostically favorable. Immunochemotherapy regimens R-B and R-CHOP are more justified in the first-line therapy of FL with low PPI3 risk. Therapy outcomes were comparable in efficacy. In intermediate and high PPI3 risk FL patients with t(14;18), the most effective first-line therapy was the one with consistent administration of R-CHOP, R-DHAP, and auto-HSCT. Based on the results of this study, FL of grades 1–3А without t(14;18) can well be considered to be a prognostically unfavorable variant of this malignant lymphoid tumor. The rate of early relapses/progression after the standard immunochemotherapy (R-B and R-CHOP), according to our data, is 60 %. In patients with newly diagnosed FL who received consistent administration of R-CHOP, R-DHAP, and auto-HSCT in the first-line therapy, this rate drops to 30 %. Our results clearly indicate the need for new FL treatment approaches.

A306 A CASE OF SCLEROSING CHOLANGITIS AS A COMPLICATION OF CAR-T THERAPY

Abstract Background Chimeric antigen receptor T-cell (CAR-T) therapy is a novel immunotherapy for treating hematological malignancies. CAR-T therapy starts with the collection of T-cells from patients. Then, receptors on the T-cell membrane are re-engineered to become chimeric antigen receptors that specifically target antigens on the surface of malignant cells. These engineered cells are grown ex vivo and infused back into the patient, leading to a targeted immune response against cancer. While CAR-T therapy has shown promising results in treating malignancies refractory to conventional treatment, there have also been reports of complications from unwanted off-target effects with CAR-T therapy. Aims We report a case of sclerosing cholangitis secondary to CAR-T therapy for the treatment of mantle cell lymphoma. Methods Case report. Results A 67-year-old male with refractory stage IVB mantle cell lymphoma underwent CAR-T therapy. His lymphoma was first diagnosed in 2011 and previous treatment included R-CHOP followed by autologous stem cell transplant. He had disease progression despite rituximab maintenance therapy and was switched to ibrutinib therapy with good response until 2023. In 2023, he was noted to have progression of his lymphoma. He subsequently underwent CAR-T therapy. His treatment was complicated by grade 2 cytokine release syndrome requiring two doses of tocilizumab. Other complications included immune effector cell-associated neurotoxicity syndrome leading to status epilepticus. He was intubated and required monitoring in the ICU however he was not in shock, nor did he require vasopressors. Post-CAR-T therapy he developed an increase of his liver enzymes in a cholestatic pattern. Magnetic resonance cholangiopancreatography (MRCP) showed irregular biliary dilation with beading suggestive of sclerosing cholangiopathy. He subsequently underwent multiple endoscopic retrograde cholangiopancreatography (ERCP) with stent insertions but there were no improvements in his liver enzymes and jaundice. A liver biopsy was performed which showed large bile duct obstruction with extensive cholestasis and some evidence of non-caseating granulomatous inflammation. Given the timing of new sclerosing cholangiopathy post-CAR-T therapy along with multiple other complications related to CAR-T therapy, it was thought this patient developed sclerosing cholangitis secondary to CAR-T therapy. Due to worsening clinical status along with progression of mantle cell lymphoma, he was transitioned to comfort care. Conclusions CAR-T therapy is a novel immunotherapy for the treatment of refractory hematological malignancies. However, complications from the off-target effects of CAR-T therapy can occur. This case highlighted a rare side effect associated with CAR-T therapy. In the future, more research will be needed to further characterize the risks associated with CAR-T therapy. Cholangiogram showing no visible filling defects or obstructive lesion. Funding Agencies None

Risk factors for hypogammaglobulinemia and association with relapse and severe infections in ANCA-associated vasculitis: A cohort study.

B-cell depletion induced by rituximab (RTX) in ANCA-associated vasculitis (AAV) is a risk factor for hypogammaglobulinemia. Aggregating data on gammaglobulin levels kinetics during RTX and its association with the risk of relapse and severe infection is of interest. Gammaglobulin levels were collected before induction therapy and during RTX maintenance therapy. We used different definitions of gammaglobulin decline: 1/gammaglobulin levels <6g/L after induction; 2/>25% decline in gammaglobulin levels between induction and maintenance, and 3/both. Our primary objective was the impact of gammaglobulin decline on the risk of relapse and severe infections. We included 98 patients. Patients with gammaglobulin level <6g/L after induction and gammaglobulin decline >25% were older (OR 3.9; 95%CI 1.1-16.1), had more frequently baseline gammaglobulin levels <10g/L (OR 6.0; 95%CI 1.7-25.8) and received more frequent pulses of methylprednisolone at induction (OR 4.6; 95%CI 1.3-18.5). Severe infection-free survival was significantly poorer in patients with both gammaglobulin <6g/L and gammaglobulin decline >25% (adjusted HR 2.3; 95%CI 1.0-5.1) and in those who received pulses of methylprednisolone (HR 5.6; 95%CI 2.3-13.4). Gammaglobulin decline was in contrast not associated with the risk of relapse. Older age, low gammaglobulin levels and pulses of methylprednisolone at induction increase the likelihood of gammaglobulin decline after induction therapy. Such decline was associated with an increased risk of severe infections but not lower risk of vasculitis relapse. Pulses of methylprednisolone at induction had an independent negative impact on gammaglobulin levels and the risk of severe infections.

Zanubrutinib, Lenalidomide Combined with R-CHOP As the Frontline Treatment for Mantle Cell Lymphoma

Objectives Mantle cell lymphoma (MCL) has poor prognosis with existing available therapies. Zanubrutinib, a novel BTK inhibitor, has shown promising outcomes in relapsed/refractory MCL. The aim of this retrospective study was to evaluate the efficacy and safety of zanubrutinib combined with R2-CHOP (lenalidomide, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in newly diagnosed MCL. Methods We retrospectively analyzed newly diagnosed MCL between September 2020, to March 2023 in a single-center in China. All patients received zanubrutinib 160 mg twice daily, lenalidomide 25 mg daily (days 1 to day 14), rituximab 375 mg/m 2, cyclophosphamide 750 mg/m 2 (day 1), doxorubicin 50 mg/m 2 or liposome doxorubicin 40 mg (day 1), vincristine 1.4 mg/m 2 (day 1), and prednisone 100 mg (day 1 to day 5) every 3 weeks. After 4 cycles, autologous hematopoietic stem cell transplantation (ASCT) was performed according to the patient's condition. After 6 cycles of induction or ASCT, patients with an objective response (complete or partial response) continued to receive zanubrutinib twice daily plus rituximab maintenance therapy, administered every 12 weeks for up to 8 additional doses. All patients underwent CT or PET-CT scans to evaluate mid-term efficacy. After 6 cycles, PET-CT scans were evaluated for patients whose mid-term efficacy did not achieve complete metabolic response (CMR). Results All of 5 patients treated with ZR2-CHOP were enrolled. The median age was 50 years (range: 44-66 years), 3 patients were females, 2 patients were males. 3 patients were classical MCL, 1 patient was pleomorphic MCL, and 1 patient was blastoid-variant MCL. The overall response rate was 100% (5 of 5), and all of them achieved CMR (Figure 1). Three patients achieved CMR after 4 cycles received ASCT, two received 6 cycles. At the mid-term evaluation after 4 cycles, 4 patients achieved CMR, 1 patient achieved PR but achieved CMR after 6 cycles. At data cutoff (22 March 2023), the median follow-up time was 26.1 (range, 12.5-32.4) months. The median PFS and OS rates were not reached. The 2-year PFS rate and the 2-year OS rates were both 100% (Figure 2). The most common grade 3/4 adverse events were neutropenia (60%) and thrombocytopenia (40%), all of which were controllable and resolved. The results of WES analysis showed that the most common gene mutations were KMT2D (frequency, 60%) and DDR2 (frequency, 40%). ctDNA was dynamically detected in four patients. Matched analysis of WES and ctDNA showed that gene mutations detected by these two methods were highly consistent, with 3 out of 4 patients being consistent. Among them, one showed negative ctDNA before and after treatment, while the other three patients indicated a decreasing trend in ctDNA mutation rate after 4 or 6 cycles, including a 50% decline or a change from baseline to negative. Conclusions: ZR2-CHOP showed promising preliminary efficacy and acceptable safety in previously untreated patients with MCL.

Trends in Survival Outcomes for Mantle Cell Lymphoma in the Era of Novel Therapies

Introduction Mantle Cell Lymphoma (MCL) is a rare malignancy, associated with aggressive features and poor outcomes. Previous treatment paradigms for MCL involved chemoimmunotherapy and stem cell transplant (SCT), though this has evolved in recent years with the introduction of novel treatments, including bruton's tyrosine kinase (BTK) inhibitors, chimeric antigen receptor T-cells (CAR-T) and immunomodulatory agents such as lenalidomide. Additionally, the incorporation of rituximab maintenance therapy following SCT has demonstrated improved progression-free (PFS) and overall survivals (OS) for MCL patients (pts). While the majority of these novel agents and treatments were FDA approved by demonstrating improved PFS, the benefits of these new treatments on OS trends for MCL pts are not well described. Therefore, to determine whether these advances have translated to OS improvement in the real-world setting, we performed a national analysis of OS trends through multiple treatment eras. Methods The National Cancer Database was used to identify pts diagnosed with MCL from 2004-2020. For pts receiving treatment, the use of front-line single or multiagent therapy, and upfront SCT was compared. Kaplan-Meier and Cox regression analysis was used to compare OS for all MCL pts. Survival was compared by year of diagnosis, with diagnosis in 2004-2013 considered to be managed in the era of chemoimmunotherapy, 2014 and later associated with the introduction of BTK inhibitors, and 2017 and later with the adoption of maintenance rituximab following SCT. Results A total of 31,284 pts with MCL were identified. The mean age at diagnosis was 67 years (yrs) [SD ±12], 93% of pts were White, and 70% had stage IV disease at diagnosis. Pts were increasingly more likely to have ≥2 comorbidities at MCL diagnosis (6.2% from 2004-2013, 8.6% from 2014-2016, and 10.8% from 2017-2020) and were increasingly managed at academic centers (40%, 44%, and 46%, respectively). Rates of pts managed with active surveillance significantly increased over time (4.7% from 2004-2013, 6.7% from 2014-2016, and 8.7% from 2017-2020). Regarding treatment, the rate of upfront multi-agent chemotherapy use decreased over time (67.7% from 2004-2013, 45.2% from 2014-2016, and 38.9% from 2017-2020), corresponding with an increase in single agent treatment (7.9%, 28.2%, and 32.4%, respectively). Notably, the rate of pts receiving SCT following front-line treatment remained similar in each time period (13.6%, 15.4%, and 14.1%, respectively). With a median follow-up of 3.5 yrs, the median OS for all pts with MCL from 2004-2020 was 5.9 yrs (95% CI 5.8-6.0 yrs). The median OS was significantly increased when comparing pts who were diagnosed between 2004-2013 (5.5 yrs) to those diagnosed 2014-2016 (6.8 yrs), and median was not reached for pts diagnosed 2017-2020 (all p&amp;lt;0.001). The median 1-, 3-, and 5-year OS significantly increased following the availability of novel agents after 2014 (2004-2013: 1-year 80%, 3-year 63%, 5-year 52% vs. 2014-2016: 1-year 82%, 3-year 67%, 5-year 58%, p&amp;lt;0.001). Whereas, pts diagnosed from 2017-2020 had similar OS trends as pts diagnosed from 2014-2016 with 1-year 82%, 3-year 66%, 5-year 51% OS, respectively. When adjusted for age and comorbidity burden, the most recent time periods were associated with decreased risk of death (2014-2016: HR 0.81 [95% CI 0.78-0.85], and 2017-2020: HR 0.82 [95% CI 0.78-0.86]) when compared to 2004-2013 (all p&amp;lt;0.001). Conclusions: To our knowledge, this is the largest retrospective review evaluating treatment trends and OS outcomes in pts with MCL in recent decades. These data show that OS has significantly improved for pts diagnosed in the most recent time periods. We hypothesize this is due to the introduction of novel agents such as BTK inhibitors, which is supported by the increased rate of single agent treatment over time, which may be related to BTK inhibitors supplanting chemoimmunotherapy in the front-line setting. We also found that no additional OS improvement was observed during the time period following the adoption of rituximab maintenance after transplant, which may be due to the limited number of pts receiving SCT through each time period. With more follow-up data, future studies may determine whether treatments such as CAR-T (FDA approved in 2020 with data not included in this cohort) have further improved OS outcomes for this incurable malignancy.

Indolent Lymphoma Care Delivery and Outcomes during the COVID-19 Pandemic in Ontario, Canada

Background At the outset of the coronavirus infectious disease 2019 (COVID-19) pandemic, hematological malignancy was recognized as a risk factor for severe COVID-19 disease, particularly patients with lymphoma, presenting a unique challenge for optimal management of indolent non-Hodgkin lymphoma (iNHL). To this end, professional societies including ASH favoured less immunosuppressive treatment regimens and omission of rituximab maintenance therapy. However, the implications of these recommendations on the care delivery and outcomes of patients with iNHL are unclear. Accordingly, we examined treatment selection, healthcare utilization, and COVID-19 outcomes of patients with iNHL receiving front line systemic treatment during pre-pandemic vs. pandemic period. Methods We performed a retrospective cohort study using administrative databases in Ontario, Canada, comparing outcomes in patients with iNHL who initiated first-line (1L) treatment with rituximab (R) monotherapy, or with bendamustine (B) or cyclophosphamide, vincristine, prednisone (CVP) from Jan 1, 2015 - Dec 31, 2018 (pre-pandemic cohort) and from Sept 1, 2019 - Aug 1, 2020 (pandemic cohort), with end of follow-up Mar, 31 2022. The primary outcome was comparison of treatment pattern before and during the COVID-19 pandemic which includes the following: 1L regimen received (R-CVP vs. B-R vs. R monotherapy), number of cycles received, dose delays, use of rituximab maintenance, and time-to-completion of full rituximab maintenance course (funded in Ontario every 3 months for 8 doses). Secondary outcomes were death, toxicities, healthcare utilization (emergency department [ED] visit, hospitalization, and ICU admission), and COVID-19 outcomes (SARS-CoV-2 PCR-confirmed infection, ED visit, hospitalization, and death). Adjusted odds ratios (aOR) and hazard ratios (aHR) with 95% confidence intervals (CI) from logistic regression and cause-specific proportional hazards models, respectively, were used to estimate associations between covariates (age, sex, comorbidity burden as measured by Aggregated Disease groups) and outcomes. Results We identified 4,143 patients (1,079 pandemic, 3,064 pre-pandemic), median age 69 (interquartile range 60-76) years, 44% female. In both pre- and pandemic periods, B-R was the most frequent prescribed regimen, with no difference in number of cycles given or in treatment delays (Table). During the pandemic, fewer patients received rituximab maintenance (69.6% vs 75.9%; aOR 0.72, 95% CI 0.60-0.88, p=0.0012). Older age was associated with lower odds of rituximab maintenance initiation (age 75+ vs. age &amp;lt; 60 aOR 0.44, 95% CI 0.35-0.56, p&amp;lt;0.0001). Moreover, patients who initiated maintenance during the pandemic period were less likely to complete the full maintenance course (48.7% vs 56.3%) (aHR 0.81, 95% confidence interval [CI] 0.71-0.92, p=0.0010) (Table) (Figure). Patients treated during the pandemic had less healthcare utilization (ED visit aHR 0.77, 95% CI 0.68, 0.88, p&amp;lt;0.0001; hospitalization aHR 0.81, 95% CI 0.70-0.94, p=0.0067) and treatment-related complications (infection aHR 0.69, 95% CI 0.57-0.82, p&amp;lt;0.0001; febrile neutropenia aHR 0.66, 95% CI 0.47-0.94, p=0.020), with no difference in death (aHR 0.79, 95% CI 0.58-1.08, p=0.14, Table). For COVID-19 outcomes, there were 131 SARS-CoV-2 infections from the beginning of the pandemic until December 31, 2021; with follow-up until March 31, 2022, there were 30 ED visits, 56 hospital admissions, and 23 ICU admissions, and 45 deaths related to COVID-19. Rituximab use (first dose to 1-year post-last dose) was associated with higher risk of COVID-19 infection (aHR 1.56, 95% CI 1.09-2.24, p=0.015) and COVID-19 complications (ED visit aHR 4.28, 95% CI 1.79-10.26, p=0.001; hospitalization/death 1.81, 95% CI 1.11-2.93, p=0.016). Primary vaccination series was associated with lower risk of infection and severe outcomes (infection aHR 0.52, 95% CI 0.28-0.97, p=0.04; hospitalization/death aHR 0.36, 95% CI 0.14-0.94, p=0.036; death aHR 0.26, 95% CI 0.07-0.89, p=0.033). Conclusion During the pandemic, B-R remained the preferred regimen for iNHL treatment, while rituximab maintenance use was less. Despite similar 1L regimen use, healthcare utilization and infectious complications were less in the pandemic cohort. Rituximab use was associated with nearly 2-fold risk of COVID-19 hospitalization/death.

Cost-minimization analysis of individually tailored or fixed-scheduled rituximab maintenance therapy for antineutrophil-cytoplasm antibody associated vasculitides

ObjectivePatients included in MAINRITSAN2 trial received either an individually tailored or a fixed-schedule therapy with rituximab as maintenance treatment of antineutrophil cytoplasm antibody associated vasculitides. The aim of this study was to compare the real-world costs of both arms. MethodWe performed a cost-minimization analysis over an 18-month time period, estimating direct costs –drug acquisition, preparation, administration and monitoring costs- from the health system perspective. We conducted a number of additional sensitivity analyses with different assumptions for unit costs, with further scenarios including the interquartile range of the tailored-infusion group results, different number of monitoring visits for fixed-schedule regimen and different number of reported severe adverse events. A cost-effectiveness analysis was conducted as a sensitivity analysis using the absolute difference in the relapse rate and its confidence interval. ResultsThe individually tailored maintenance therapy with rituximab was shown to be a cost-saving treatment compared to the fixed-schedule therapy (6,049 euros vs. 7,850 euros). Savings resulted primarily from lower drug acquisition costs (2,861 vs. 4,768 euros) and lower preparation and administration costs (892 vs. 1,486 euros), due to the lower number of infusions per patient in the tailored-infusion regimen. The tailored-infusion regimen presented higher monitoring costs (2,296 vs. 1,596 euros). This result was replicated in all assumptions considered in the sensitivity analysis of cost-minimization approach. ConclusionsFrom the perspective of the health system, the tailored-therapy regimen seems to be the preferable option in terms of direct costs. Further studies assessing all the effects and costs associated to vasculitides maintenance treatment with rituximab are needed to support clinical management and healthcare planning.

Incidence of Pneumocystis Jiroveci Pneumonia in Patients With ANCA-Associated Vasculitis Initiating Therapy With Rituximab or Cyclophosphamide.

This manuscript assesses the incidence of Pneumocystis jiroveci pneumonia (PJP) among patients receiving contemporary treatment regimens for antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and adverse events associated with PJP prophylaxis. Incident users of rituximab or cyclophosphamide for AAV were identified in the TriNetX electronic health records database from 2011 to 2022. The incidence rates (IRs) of PJP in the first 6 months of induction therapy with rituximab and/or cyclophosphamide and during postinduction maintenance therapy with rituximab were calculated. Cox proportional hazard models were used to estimate hazard ratios (HRs) and confidence intervals (CIs) for the risk of adverse events commonly associated with PJP prophylaxis. We identified 1,461 AAV cases who received induction therapy with rituximab (69.7%), cyclophosphamide (18.9%), or both (11.4%). Prophylaxis prescribed within 30 days of induction included trimethoprim-sulfamethoxazole (30.7%), atovaquone (5.4%), dapsone (3.8%), and pentamidine (0.8%). During induction therapy, 10 cases of PJP were identified (IR 15.0 cases per 1,000 patient-years); no deaths occurred. In adjusted analyses, those who received prophylaxis had a higher risk of leukopenia (HR 3.1; 95% CI 1.1-8.6), rash (HR 1.9; 95% CI 1.0-3.6), and nephropathy (HR 2.6; 95% CI 1.3-5.1) than those who did not.During rituximab maintenance therapy (n=709), five cases of PJP were identified (IR 2.1 cases per 1,000 person-years), one of whom died during the hospitalization associated with a PJP diagnosis. Rates of PJP in patients with AAV were lower than previously observed, and few cases occurred during rituximab maintenance therapy. PJP prophylaxis was associated with adverse events.

Reduced-dose versus high-dose glucocorticoids added to rituximab on remission induction in ANCA-associated vasculitis: predefined 2-year follow-up study

ObjectivesThe LoVAS trial reported non-inferiority in remission induction rates between the reduced-dose and conventional high-dose glucocorticoid regimens plus rituximab for antineutrophil cytoplasm antibody (ANCA)-associated vasculitis at 6 months; however, maintenance...

Association between plasma rituximab concentration and the risk of major relapse in antineutrophil cytoplasmic antibody-associated vasculitides during rituximab maintenance therapy.

Interindividual variability in response to rituximab remains unexplored in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides. Rituximab pharmacokinetics (PK) and pharmacodynamics (PD) as well as genetic polymorphisms could contribute to variability. This ancillary study of the MAINRITSAN 2 trial aimed to explore the relationship between rituximab plasma concentration, genetic polymorphisms in PK/PD candidate genes, and clinical outcomes. Patients included in the MAINRITSAN2 trial (NCT01731561) were randomized to receive a 500 mg fixed-schedule RTX infusion or an individually-tailored regimen. Rituximab plasma concentrations at month 3 (CM3 ) were assessed. DNA samples (n=53) were genotyped for single nucleotide polymorphisms within 88 putative PK/PD candidate genes. The relationship between PK/PD outcomes and genetic variants was investigated using logistic linear regression in additive and recessive genetic models. One hundred and thirty-five patients were included. The frequency of underexposed patients (<4 μg/mL) in the fixed-schedule group was statistically lower compared to that in the tailored-infusion group (2.0% vs. 18.0%; p=0.02, respectively). Low RTX plasma concentration at 3 months (CM3 <4 μg/mL) was an independent risk factor for major relapse (odds ratio=6.56; 95% CI 1.26-34.09; p=0.025) at month 28 (M28). A sensitivity survival analysis also identified CM3 <4 μg/mL as an independent risk factor for major relapse (Hazard ratio [HR] = 4.81; 95% CI 1.56-14.82; p=0.006) and relapse (HR=2.70; 95% CI 1.02-7.15; p=0.046). STAT4 rs2278940 and PRKCA rs8076312 were significantly associated with CM3 but not with major relapse onset at M28. These results suggest that drug monitoring could be useful to individualize the schedule of rituximab administration within the maintenance phase. This article is protected by copyright. All rights reserved.

Clinical Images: Optic perineuritis in relapsing granulomatosis with polyangiitis.

The patient, a 76-year-old man who was previously diagnosed as having granulomatosis with polyangiitis (GPA) and was receiving rituximab maintenance therapy every 6 months, presented with malaise, night sweat, transient lockjaw, and right-sided facial pain and swelling following dental extraction 2 weeks earlier. He subsequently developed retrobulbar pain, conjunctival injection, chemosis, and fluctuating visual impairment. T1-weighted contrast magnetic resonance imaging (MRI) of the orbit revealed contrast enhancement of the right optic nerve sheath sparing the optic nerve itself (“doughnut sign”) consistent with optic perineuritis (coronal image in A; axial image in B). Laboratory evaluation showed elevated C-reactive protein (276 mg/liter) and leukocytosis (13,430/μl) (Supplementary Table 1, http://onlinelibrary.wiley.com/doi/10.1002/art.42426). Blood cultures and cerebrospinal fluid analysis including mycobacterial and fungal polymerase chain reaction showed no evidence of infection. Moreover, empirical antibiotic therapy did not result in clinical improvement. In GPA, optic neuropathy accompanied by retrobulbar pain and/or oculomotor nerve palsy usually occurs as a result of compression by inflammatory orbital masses (1, 2). However, it may rarely be encountered due to posterior ischemic neuropathy, optic neuritis, and/or perineuritis without inflammatory pseudotumor (1). Imaging may reveal signs of pachymeningitis, often subtle, and additional orbital apex infiltration (1-3). In some patients, high levels of inflammation markers can be detected (1, 2). Optic perineuritis has a poor prognosis with frequent recurrence of symptoms following reduction of glucocorticoid dose, thus requiring aggressive immunosuppressive treatment with cyclophosphamide and/or rituximab (1, 2). In our patient, immunosuppressive therapy was switched to combined rituximab and pulse cyclophosphamide treatment with the addition of a glucocorticoid for the re-induction of remission, resulting in protracted resolution of clinical symptoms and MRI findings (Supplementary Figure 1, http://onlinelibrary.wiley.com/doi/10.1002/art.42426). Disclosure Form Supplementary Figure 1: MRI follow-up showing resolution of contrast enhancement of the right optic nerve sheath following re-induction of remission with combined rituximab and pulse cyclophosphamide treatment and addition of glucocorticoid (A coronal image, B axial image). Supplementary Table 1: Laboratory values Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Lenalidomide Consolidation Added to Rituximab Maintenance Therapy in Patients Remaining PET Positive After Treatment for Relapsed Follicular Lymphoma: A Phase 2 Australasian Leukaemia & Lymphoma Group NHL26 Study.

Lenalidomide Consolidation Added to Rituximab Maintenance Therapy in Patients Remaining PET Positive After Treatment for Relapsed Follicular Lymphoma: A Phase 2 Australasian Leukaemia & Lymphoma Group NHL26 Study.

PS-R05-1: CASE REPORT: A RARE CASE OF ALVEOLAR HEMORRHAGE AFTER COVID-19 VACCINATION IN A PATIENT WITH RENAL-LIMITED ANTI-NEUTROPHIL CYTOPLASMIC ANTIBODY-ASSOCIATED VASCULITIS

The coronavirus disease 2019 (COVID-19) vaccination campaign has progressed worldwide. Rare but severe adverse events of COVID-19 vaccination such as anaphylaxis and myocarditis have begun to be noticed. Of note, several cases of new-onset antineutrophil cytoplasmic antibody-associated vasculitis (AAV) after COVID-19 mRNA vaccination have been reported. In contrast, relapse of AAV in remission has not been recognized enough as an adverse outcome of COVID-19 vaccination. We report, to the best of our knowledge, a first case of renal-limited AAV in remission using every 6-month rituximab administration that relapsed with pulmonary hemorrhage, but not glomerulonephritis, following the first dose of the COVID-19 vaccine. Notably, the patient received the COVID-19 vaccine more than 6 months after the last dose of rituximab according to the recommendations. Ironically, his CD19 positive B cell counts were found to be increased after admission, indicating that our case might have been prone to relapse after COVID-19 vaccination. Although our case cannot establish causality between AAV relapse and COVID-19 mRNA vaccination, a clinical vigilance for relapse of AAV especially in patients undergoing rituximab maintenance therapy following COVID-19 vaccination should be maintained. Furthermore, the elapsed time between rituximab administration and COVID-19 mRNA vaccination should be carefully adjusted based on AAV disease-activity (Nishioka et al. Front Med 2022. in press). JOURNAL/jhype/04.03/00004872-202301001-01135/figure1/v/2023-10-24T163949Z/r/image-jpeg

Baseline PET Metabolic Tumor Volume Predicts Outcome in Advanced Follicular Lymphoma Patients Who Received First-Line Immunochemotherapy but Not Those Treated with Lenalidomide-Rituximab in the Phase III Relevance Study

Introduction The prognostic value of total metabolic tumor volume (TMTV) at diagnosis in follicular lymphoma (FL) remains debated. Its impact was reported for patients treated mostly with Rituximab (R)-CHOP chemotherapy without R maintenance (FOLLCOLL study, Meignan et al, J Clin Oncol. 2016; 34(30):3618-3626) but manual TMTV assessment was not confirmed as prognostic in the GALLIUM trial where most patients had bendamustine and anti-CD20 antibody maintenance (Barrington et al, Blood 2018; 132(Suppl 1):2882). There is no data on the prognostic value of TMTV in chemo-free regimens such as the immunomodulatory combination of lenalidomide and rituximab (R2). Here, we investigated the prognostic value of baseline TMTV for FL patients with previously untreated advanced FL included in in the phase 3 RELEVANCE trial comparing R2vs R-chemo with both regimens followed by rituximab maintenance therapy (NCT01476787 and NCT01650701). Methods TMTV was computed on baseline PET/CT using the 41% SUVmax method. To separate high and low TMTV, we tested the previously published cut-off of 510cm3 (Meignan et al. J Clin Oncol. 2016; 34(30):3618-3626). Survival was estimated using Kaplan Meier curves. Analyses were performed on the total PET-evaluable population (n=406/1032) with 196 pts on the R2 arm and 210 pts on the R chemo arm, because baseline PET was not mandatory in this trial. Results Clinical baseline characteristics of PET evaluable patients were similar to the overall trial population for age, Ann Arbor stage, bone marrow infiltration, LDH, beta 2 microglobulin and FLIPI, and well balanced between the two treatment arms. After a median 6.5 years follow-up, 5y-PFS was 67.6%, 5y-OS was 93.5%, with no significant difference between the two arms. Median baseline TMTV was 284 cm3 in the whole cohort (Q1-Q3; 144-553) : 274 cm3 (129-526) in the R2 arm and 288 cm3 (148-562) in the R chemo arm (p=0.579). Overall, patients with TMTV > 510 cm3 had higher Ann Arbor stage (p<0.001), more extra nodal sites (p<0.001), more frequently elevated beta 2 microglobulin (p<0.001), higher FLIPI (p=0.002) and FLIPI2 scores (p<0.001). High TMTV was significantly associated with an inferior PFS (p=0.0121) and POD 24 (p=0.0014) but not OS (p=0.247). Patients with a high TMTV (n=111, 27%) had a 5-year PFS of 53.9% (CI 95% 43.6-63.1) vs 70.5% (CI 95% 64.7-75.6) for low TMTV patients. By contrast, bulk as measured by CT (either >6cm or >7cm) was not prognostic of PFS (p=0.978 and p=0.661 respectively). When testing FLIPI with TMTV both were independently associated with PFS (p=0.0119 and p=0.0379, respectively). When testing FLIPI2 with TMTV, only TMTV remained significant (p=0.2444 for FLIPI2, p=0.0285 for TMTV). The combination of FLIPI and TMTV stratified the overall population into 3 risk groups : patients with no risk factors had a 5y-PFS of 76.3% (n=162, 40% reference), declining to 63.4% for patients with 1 risk factor (n=180, 44%; HR=1.45 ;[1.01-2.06], p=0.042) and 47.1% (n=64, 16%; HR=2.15 [1.39-3.31], p<0.001) for patients with both. Although the interaction between TMTV and randomization arm was not statistically significant for PFS (p=0.31), the prognostic impact of TMTV appeared different between the two arms: a high TMTV was associated with a lower PFS in the R chemo arm (Figure 1 A: p=0.0093) whereas it was not significant in the R2 arm (Figure 1B: p=0.3369). Conclusion: Baseline TMTV was a strong prognostic factor independent of FLIPI or FLIPI2 status, in advanced FL patients treated with first-line immunochemotherapy followed by antibody maintenance but not R2. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Rituximab-induced interstitial pneumonitis in patient with non-Hodgkin lymphoma: a clinical case

Rituximab is a chimeric monoclonal antibody against CD20+ lymphocytes used to treat non-Hodgkin lymphoma, hematological and autoimmune diseases rheumatoid arthritis, systemic lupus erythematosus, thrombocytopenic purpura, hemolytic anemia, multiple sclerosis. The safety of the drug is critical to the choice of treatment. Rituximab-associated interstitial lung disease is rare.&#x0D; Objective. To describe a case of interstitial pneumonitis induced by rituximab in monotherapy at the end of maintenance therapy.&#x0D; Materials and methods. We describe a case of a 37-year-old patient with stage IIB non-Hodgkin lymphoma involving palatine tonsils and cervical and submandibular lymph nodes on both sides. Histologically, this tumor was a diffuse large B-cell lymphoma.&#x0D; Results. A patient received six R-CHOP courses of chemotherapy and immunotherapy for stage IIB diffuse large B-cell lymphoma. After the therapy, a complete clinical and metabolic response was achieved. Rituximab maintenance therapy was administered at a dose of 375 mg/m2 every 2 months for 2 years. At this treatment stage, combined positron emission tomography and 18F-fluorodeoxyglucose computed tomography (PET/CT with 18F-FDG) was performed at 45 months intervals. No radiological signs of pulmonary diseases were detected. Seven weeks after the last dose of rituximab (24 months), another PET/CT with 18F-FDG showed radiological changes that were considered to be interstitial pneumonitis, with no respiratory signs of the disease. No signs of tumor progression were found.&#x0D; Conclusion. Rituximab may contribute to late pulmonary toxicity presented as interstitial pneumonitis in non-Hodgkin lymphoma patients at a young age after maintenance therapy for 24 months. PET/CT with 18F-FDG is the primary method of diagnosing pulmonary toxicity.

65-Year-Old Man With Weight Loss and Dyspnea on Exertion

65-Year-Old Man With Weight Loss and Dyspnea on Exertion

Ibrutinib plus Bendamustine and Rituximab in Untreated Mantle-Cell Lymphoma

BackgroundIbrutinib, a Bruton’s tyrosine kinase inhibitor, may have clinical benefit when administered in combination with bendamustine and rituximab and followed by rituximab maintenance therapy in older patients with untreated mantle-cell lymphoma.MethodsWe randomly assigned patients 65 years of age or older to receive ibrutinib (560 mg, administered orally once daily until disease progression or unacceptable toxic effects) or placebo, plus six cycles of bendamustine (90 mg per square meter of body-surface area) and rituximab (375 mg per square meter). Patients with an objective response (complete or partial response) received rituximab maintenance therapy, administered every 8 weeks for up to 12 additional doses. The primary end point was progression-free survival as assessed by the investigators. Overall survival and safety were also assessed.ResultsAmong 523 patients, 261 were randomly assigned to receive ibrutinib and 262 to receive placebo. At a median follow-up of 84.7 months, the median progression-free survival was 80.6 months in the ibrutinib group and 52.9 months in the placebo group (hazard ratio for disease progression or death, 0.75; 95% confidence interval, 0.59 to 0.96; P=0.01). The percentage of patients with a complete response was 65.5% in the ibrutinib group and 57.6% in the placebo group (P=0.06). Overall survival was similar in the two groups. The incidence of grade 3 or 4 adverse events during treatment was 81.5% in the ibrutinib group and 77.3% in the placebo group.ConclusionsIbrutinib treatment in combination with standard chemoimmunotherapy significantly prolonged progression-free survival. The safety profile of the combined therapy was consistent with the known profiles of the individual drugs. (Funded by Janssen Research and Development and Pharmacyclics; SHINE ClinicalTrials.gov number, NCT01776840.)