Partial Renal Response Research Articles

Clinical outcomes in lupus nephritis patients treated with belimumab in real-life setting: a retrospective comparative study in China.

The use of belimumab in treating lupus nephritis (LN) patients in China is still in its early stages. This retrospective comparative study aims to delineate the disease activity, associated therapies, clinical outcomes, and adverse events among LN patients treated with belimumab, reflecting real-world experience in southeastern China. From May 2020 to December 2023, 54 LN patients treated with belimumab and 42 LN patients treated with conventional therapy were enrolled. All patients had a follow-up period of more than 3 months. The general information, presenting clinical and laboratory data, and outcomes were collected and compared. At 3 months of belimumab treatment, compared to baseline, there was a decrease in proteinuria from 74.1% to 64.8% (p<0.001), a reduction in hematuria from 59.3% to 37.0% (p=0.008), and an increase in partial or complete renal response from 53.7% to 75.9% (p<0.001). The median SLEDAI score decreased from 10 to 5 (p<0.001), and the proportion of patients achieving low lupus disease activity state (LLDAS) increased from 11.11% to 16.67% (p<0.001) by the 3-month evaluation. Notably, there were significant reductions in oral corticosteroid dosages, with a median decrease from 30 to 17.5 mg/day (p<0.001) by 3 months, and the proportion of patients requiring >5 mg/day of steroids decreased from 88.89% at baseline to 79.07% at six months (p<0.001). Compared to the conventional therapy group, the belimumab group experienced a significant reduction in median steroid dosage and increased the proportion of patients achieving remission or LLDAS. The incidence of treatment-emergent adverse events (TEAEs) was significantly lower in the belimumab group (29.6% vs 52.4%, p=0.024). These findings support the potential of belimumab to improve renal and serological parameters, reduce disease activity, lessen corticosteroid dependence, and decrease the risk of TEAEs, demonstrating its safety and efficacy as an adjunct therapy in LN management.

Lupus nephritis. Part II, modern ideas about therapy

The second part of the review presents current data on the treatment strategy for lupus nephritis, considering the morphological class of kidney damage, course and activity. Approaches to monitoring and evaluating the effectiveness of treatment, the problems of achieving a complete and partial renal response are described. The characteristic of classical and innovative methods of therapy is given.

Sustained depression of B cell counts in lupus nephritis after treatment with rituximab and/or belimumab is associated with fewer disease flares.

To study the risk of lupus nephritis flare (LNF) or severe lupus flare (SLF) as a function of B cell count kinetics in lupus nephritis (LN) patients after they achieve at least a partial renal response (PRR) with induction treatment that includes rituximab (RTX) and/or belimumab (BLM). We performed a retrospective analysis of a cohort of 19 patients with severe LN that received a B cell agent (BCA), RTX and/or BLM, as part of an initial treatment regimen for an LN flare and had subsequent CD19+ B cell measurements in peripheral blood. We then characterized the follow-up periods, after B cell depressions occurred and PRR were achieved, by the corresponding trajectories of B cell counts (BCC). Time periods with sustained low BCC were type 1 (T1) episodes, while those with repletion of BCC>100 cells/μL were called type 2 (T2) episodes. Time periods with rapid BCC repletion, defined as >50 cells/μL in ≤6months, were called T2b episodes. Corresponding C3, C4, and anti-dsDNA levels were recorded for each episode. The time from PRR until an event, either a LNF or SLF, or to censoring, either at the end of the study period or the end of available patient follow-up, was assessed for each episode type. Kaplan-Meier survival analysis was used to compare time to flare between T1 and T2 episodes. There were 26 episodes of B cell depression. Seventeen (65%) were T1 and 9 (35%) were T2. Compared to T1 episodes, T2 episodes were 9.0 times more likely to result in flare over the follow-up period (hazard ratio (HR) = 9.0, 95% CI for HR = 2.2-36.7); this risk was even larger for T2b vs T1 episodes. Median BCC was 14 cells/μL in T1 and 160 cells/μL in T2 episodes. Both C3 and C4 levels significantly increased over the duration of the episode in T1 episodes only. Sustained low BCC was associated with prolonged serologic and clinical response, whereas repletion, and particularly rapid repletion, of B cells after treatment with BCA was associated with subsequent disease flare.

#1297 Approaches to renal response assessment in rare monoclonal immunoglobulin related glomerulopathies

Abstract Background and Aims AL-amyloidosis (AL) and monoclonal immunoglobulin (MIg) deposition disease are common types of MIg-related glomerulopathies (MIgG) and are well-studied including approaches to treatment and hematological and renal responses (RR) assessment. Other rare MIgG comprise very diverse patterns of glomerular injury e.g. proliferative glomerulonephritis with MIg deposition (PGNMID), C3-glomerulopathy, fibrillary glomerulonephritis etc. Although RR defined as decrease in 24 h proteinuria by 30% without kidney function decline was validated only for renal AL it is widely used for MIg deposition disease and rare MIgG without validation. Nevertheless, the best approach to RR assessment in rare MIgG is still unclear. To shed some light on this problem we performed this study. Method We retrospectively analyzed 31 patients with rare MIgG who were treated with clone-specific treatment and had available follow-up (FUP) ≥6 months (mo). The following morphological patterns were diagnosed: PGNMID (n = 9), C3-glomerulopathy (n = 9), thrombotic microangiopathy (n = 5), cryoglobulinemic glomerulonephritis (n = 3), fibrillary glomerulonephritis (n = 3), immunotactoid glomerulonephritis (n = 1) and membranous nephropathy (n = 1). Patients’ baseline parameters are shown on Fig. 1 as well as treatment modalities. Hematological response defined according to currently accepted criteria is demonstrated on Fig. 1. We evaluated two approaches to the RR assessment: 1) at least partial renal response (PR) defined as 24 h proteinuria decreased by 50% from the baseline and &amp;lt;3.5 g, and 2) according to Palladini's criteria for AL (AL-RR) i.e. 24 h proteinuria decreased by 30% from the baseline or &amp;lt;0.5 g. Both RR were considered as achieved only in the absence of estimated glomerular filtration rate (eGFR) decline &amp;gt;25%. Time points for RR assessment were 6, 12 and 24 mo from the clone-specific treatment initiation. Renal outcome was estimated as initiation of renal replacement therapy or eGFR &amp;lt;15 ml/min/1.73 m2 at the end of follow-up. Death-censored renal survival was analyzed by the Kaplan-Meier method. Cox regression analysis was applied to determine which RR was independently associated with long-term kidney outcome. P-value was assumed at &amp;lt;0.05. Median FUP was 19 (7; 50) mo. FUP ≥12 and ≥24 mo were available in 26 and 17 patients, respectively. Results Total number of patients who achieved AL-RR at any RR assessment time point was 22 (71%). At 6, 12 and 24 mo the achievement of AL-RR was registered in 17, 16 and 10 patients, respectively. PR cumulatively was achieved in 19 (61%) patients: at time points of 6, 12, and 24 mo it was registered in 14, 14 and 9 cases, respectively. The 5-year cumulative renal survival in those who had AL-RR was better than in not responders (Fig. 2A). Patients who ever achieved PR had better cumulative renal survival compared with patients with no renal remission (Fig. 2B). In univariate Cox regression analysis the achievement of AL-RR (Exp(β) 0.158 (95% CI 0.03; 0.819)) was associated with renal outcome as well as the achievement of PR (Exp(β) 0.074 (95% CI 0.09; 0.626)). In multivariate Cox regression model adjusted for eGFR at the time of kidney biopsy AL-RR vs no response was estimated as an independent predictor of renal long-term prognosis (Exp(β) 0.082 (95% CI 0.009; 0.725)) as well as eGFR (Exp(β) 0.89 (95% CI 0.821; 0.985)). The only independent predictor of renal outcome in the model including eGFR at the time of kidney biopsy (Exp(β) 0.85 (95% CI 0.72; 0.99), p = 0.05) was PR (Exp(β) 0.011 (95% CI 0; 0.547), p = 0.021). Conclusion The classical concept of complete and partial renal remission seems to be more appropriate for rare MIgG and requires further validation studies.

#2244 Safety and efficacy of daratumumab monotherapy in lupus nephritis refractory to conventional and rescue therapies

Abstract Background and Aims Refractory lupus nephritis (LN) is defined as either no response to standard of care (SOC), i.e., failure to improve within 3–4 months or not achieving partial response within 12 months or complete response after 2 years of treatment. This condition is characterized by poor outcome, is often life-threatening, and represents a relatively unexplored clinical setting. A dysregulation of CD38 expression has been reported in Systemic lupus Erythematosus, and highly expressing CD38 plasma cells relegated in bone marrow niches inaccessible to conventional and biological agents could represent a source of repowering of the immune dysregulation. The efficacy and safety of daratumumab, a monoclonal antibody specifically directed at CD38, given without any other immunosuppressant or agents targeting B-cell-activating factor, were assessed in a discrete cohort of patients with refractory LN, in whom both SOC and rescue treatments had failed. Method Six patients (1 male and 5 females) aged 41.3 years (range 20 to 61 years) were treated with Daratumumab monotherapy. The treatment protocol consisted of 16 mg/kg daratumumab administered intravenously weekly for 8 weeks, then every two weeks 8 more times, and lastly monthly for 8 times. All patients had failed previous treatments with both SOC including either mycophenolate mofetil or cyclophosphamide-azathioprine, and rescue therapies including Rituximab, Ocrelizumab, Belimumab, and iv IgG. Results One out of six patients did not show clinical response after 6 months of therapy, and Daratumumab was discontinued. Five patients continued to be treated (total treatment maximum 22 infusions) and reached a 12-month observation. Renal biopsy performed before daratumumab administration revealed a class IV LN in 1 patient, class V LN in 1 patient, class III+V LN in 1 patient and class IV+V LN in the other 2. Three patients achieved a complete renal response and the other two a partial renal response. A significant decrease in proteinuria from 5.6 g per 24 h to 0.59 g per 24 h, 0.9 g per 24 h and 0.8 g per 24 h (P = 0.0010) at 3 months, 6 months and 12 months, respectively, was observed. The mean value of serum Creatinine (sCr) decreased from 2.3 to 1.5 mg/dl. The mean value of sCr decreased from 2.3 mg dl−1 to 1.5 mg/dl (P = 0.98) at 12 months. C3 and C4 levels increased from 72.8 (range, 0–99) to 101.6 (range, 78.0–135) mg/dl (P = 0.16) and from 9.4 (range, 5–14) to 20.4 (range, 13–30) mg/dl (P = 0.0182), respectively. A decrease in IgG mean levels from 971.7 mg dl−1 (range, 251–1546) to 512.3 mg/dl (range, 88–957), 481.7 (range, 84–878) mg/dl and 508.4 mg/dl (range, 192–685) at 3 months, 6 months and 12 months, respectively, was observed. Improvement of clinical symptoms was paralleled by seroconversion of anti-double-stranded DNA antibodies (p = 0.03), significant decrease in interferon-gamma values (p = 0.0006), BMCA-B-cell maturation antigen (p = 0.0005) and soluble CD163 levels (p = 0.045), and IL 10 levels (p = 0.0006). Clinical remission was substantiated by improvement of SLEDAI-2K score (p = 0.03). Daratumumab was generally well tolerated. Conclusion These data suggest that Daratumumab administered alone (i.e., without any other immunosuppressant or agents targeting B-cell activating factor) is highly effective in refractory LN. The multifaced effects of Daratumumab on the inflammatory burden and the interferon gamma profile could provide a restoration of the immune balance.

#1505 Late-onset lupus nephritis: clinical-epidemiological, histological, prognostic and therapeutical implications: a single center experience

Abstract Background and Aims Systemic lupus erythematosus (SLE), a chronic autoimmune disease, and lupus nephritis (LN), are typically diagnosed in women in fertile age. Late-onset SLE is defined as a disease onset over 50 years. Our main objective was to analyze the clinical, histological, prognostic and therapeutical features related to LN in our late-onset SLE population. Method A single center and retrospective study was performed comparing clinical-demographic, histological, prognostic and therapeutical data of 45 LN biopsied patients from 1994 to 2023. We divided the study population according to the age of onset of LN into classic-onset (&amp;lt; 45 years) and late-onset (&amp;gt; 45 years). Results Late-onset LN patients showed a higher association with Sjögren's and antiphospholipid syndrome, more cardiovascular comorbidities at presentation, poorer renal function at diagnosis and higher SDI score. On histology they showed more non-proliferative LN classes (II followed by V). Late-onset LN responders needed more time to achieve response but had fewer relapses. Non responsive patients had more incidence of acute kidney injury (AKI) and more glomerulosclerosis and interstitial fibrosis-tubular atrophy (IFTA) at presentation, as well as more need for renal replacement therapy (RRT) at diagnosis and at follow-up. The principal independent variables associated with relapse were the younger age at SLE diagnosis and an initial partial renal response (PRR). Patients of both groups who experienced relapse received higher doses of intravenous cyclophosphamide and less mycophenolic acid (MFA) analogues. Patients who received induction with MFA analogues were more likely to achieve complete renal response (CRR) or non-renal response (NRR). Conclusion late-onset LN is often accompanied by poor renal function at presentation. It seems imperative to establish a tailored approach in this fragile population in order to avoid unnecessary immunosuppression.

#1153 Short course of steroids as a treatment for immune checkpoint inhibitors-associated acute kidney injury

Abstract Background and Aims Immune checkpoint inhibitors (ICPi) have been a revolution in oncology. Due to their mechanism of action they can produce inflammatory adverse events, called “immune related adverse events” (IrAEs). Immune-mediated renal toxicity appears to be infrequent (2.2-5%), with acute tubulointerstitial nephritis being the most common form, clinically manifested as acute kidney injury (AKI). Corticosteroids are a highly effective treatment. However, the most suitable regimen has not been established. Method Retrospective multicenter study to evaluate the efficacy and safety of a short course of steroids (Group A) versus a long course (Group B) in patients with a clinical or histologic diagnosis of ICPi-associated acute kidney injury (ICPi-AKI). Short-duration regimen was considered to be that with a duration ≤3 months. Renal response was assessed 3 months after initiation of steroid therapy. Partial and complete renal response rates were compared in both groups, as well as relapses of ICPi-AKI with the lowering or suspension of steroid treatment. The development of adverse effects attributable to corticosteroids and the evolution of the oncologic disease were also evaluated. Results Sixty-three patients were included, 30 (48%) of whom received a short course of corticosteroids. Type of malignancy and oncologic treatment were similar in both groups. Baseline serum creatinine (1.1 mg/dL Group A and 0.9 mg/dL Group B; p = 0.53) and at ICPi-AKI diagnosis (3.0 mg/dL in Group A and 2.8 mg/dL in Group B; p = 0.43) were comparable. As shown in the table below, cumulative prednisone dose was lower in Group A than in Group B (1654 mg vs 4030 mg; p = 0.001). The overall renal response was 92% (87% Group A and 97% Group B; p = 0.2). There were no differences in complete response (40% Group A and 40% Group B; p = 1) or partial response (47% Group A and 57% Group B; p = 0.4). There were no recurrences of AKI after rechallenge of ICPi treatment. Adverse events related to corticosteroids were similar. There was a trend towards greater progression of oncologic disease in group B (64% versus 40%; p = 0.08). Conclusion A short course of steroids (&amp;lt; 3 months) is equally effective as a treatment for ICPi-AKI as longer courses, both in terms of renal response and relapse rate of ICPi-AKI. Adverse events related to steroid treatment were comparable in both groups. There appeared to be greater oncologic progression in the prolonged steroid treatment group.

Evaluating the cost-effectiveness of voclosporin for the treatment of lupus nephritis in the United States.

Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus; up to 30% of patients with LN will develop end-stage kidney disease (ESKD). One of the main treatment goals for LN is preservation of kidney function, with early decreases in proteinuria associated with improved long-term outcomes. Voclosporin, a second-generation calcineurin inhibitor, was approved in the United States in 2021 for the treatment of active LN combined with background immunosuppression. The AURORA 1 study found that the use of voclosporin with low doses of mycophenolate mofetil and glucocorticoids yielded significant reductions in proteinuria. The AURORA 2 study showed long-term efficacy and safety of voclosporin over a 3-year period with kidney function preservation. The Institute for Clinical and Economic Review (ICER) is a nonprofit organization that evaluates medical evidence to help improve patient outcomes and control costs. In 2021, ICER published an economic model to estimate the impact and cost-effectiveness of LN therapies. From a US health care perspective, voclosporin was cost-effective at $149,260 per quality-adjusted life-year (QALY) and $131,528 per equal value of life-years gained (evLYG). At the time of the LN cost-effectiveness model (CEM) development, voclosporin was not yet approved in the United States and the cost of treating patients with LN with ESKD was not captured in the literature. To evaluate the cost-effectiveness of voclosporin given the emergence of new data. The LN CEM uses a short-term trial-based Markov model and long-term extrapolation using partitioned survival modeling data assuming adults with LN start with active disease, transitioning to complete or partial renal response, kidney failure, or death. In the current analysis, clinical data for voclosporin, duration of voclosporin treatment for nonresponders, and drug costs reflecting the 2023 price of voclosporin were updated. Additionally, health care payer costs of disease management were incorporated based on real-world claims data on the costs of treating patients with LN. Using the LN CEM with inputs reflecting the latest and most relevant evidence, the incremental cost of voclosporin per QALY was $88,076 and per evLYG was $77,643. For a subpopulation of Black, Hispanic, and Latino patients, the incremental cost of voclosporin per QALY was $77,435 and per evLYG was $67,828. Following the inclusion of updated data in the cost-effectiveness analysis, voclosporin remains a cost-effective therapy for the treatment of active LN including in a Black, Hispanic, and Latino subpopulation, substantially below the ICER willingness-to-pay threshold of $150,000/QALY.

Combination of anti-SSA/Ro60 and anti-dsDNA serotype is predictive of belimumab renal response in patients with lupus nephritis

ObjectivesTo investigate the effectiveness of belimumab on active lupus nephritis (LN) and explore the predictors, including serological biomarkers, of renal response to belimumab in a real-world setting.MethodsThis multicentre, real-world observational...

Rituximab treatment in resistant lupusnephritis: A single-center prospective study.

Lupus nephritis (LN) is a serious manifestation of systemic lupus erythematosus (SLE) and failure to respond to traditional immunosuppression increases morbidity and mortality. Rituximab has been considered a novel therapeutic option for the management of SLE. We conducted a single-center, prospective, observational study from July 2018 to June 2019 to evaluate the effectiveness of rituximab in patients with resistant LN. Resistant LN was defined as the failure to respond to conventional immunosuppressive therapy including both cyclophosphamide and mycophenolate mofetil. All adult patients (>18 years) with biopsy-proven class III/IV LN were included in the study. Four doses of intravenous rituximab (375 mg/m2) on 0, 1, 2, 3 weeks were administered. Patients were followed for 6months, and the rates of complete renal response (CRR), partial renal response (PRR), or no renal response (NRR) were measured. The change in baseline 24-hour urine protein, mean serum creatinine levels, and mean serum CD-19 levels at 24 weeks were also measured. Six months after rituximab therapy, total sustained renal response (CRR+PRR) was observed in 52% cases of resistant LN (CRR was achieved in 24% of patients and PRR in 28%, respectively). Rituximab was associated with a significant decline in the 24-hour urine protein, even in non-responders. However, the improvement in eGFR and serum creatinine was not statistically significant. The mean absolute CD-19 count was significantly low in responders compared to the non-responder group. Rituximab is a safe and effective therapeutic strategy for patients with resistant LN.

Renal Response Outcomes of the EuroLupus and National Institutes of Health Cyclophosphamide Dosing Regimens in Childhood-Onset Proliferative Lupus Nephritis.

We compared clinical characteristics and renal response in patients with childhood-onset proliferative lupus nephritis (LN) treated with the EuroLupus versus National Institutes of Health (NIH) cyclophosphamide (CYC) regimen. A retrospective cohort study was conducted at 11 pediatric centers in North America that reported using both CYC regimens. Data were extracted from the electronic medical record at baseline and 3, 6, and 12 months after treatment initiation with CYC. To evaluate the adjusted association between CYC regimen (EuroLupus vs NIH) and renal response over time, generalized estimating equations with a logit link were used. An interaction between time and CYC regimen was included, and a contrast between CYC regimens at 12 months was used to evaluate the primary outcome. One hundred forty-five patients (58 EuroLupus, 87 NIH) were included. EuroLupus patients were on average older at the start of current CYC therapy, had longer disease duration, and more commonly had relapsed or refractory LN compared with the NIH group. After multivariable adjustment, there was no significant association between CYC regimen and achieving complete renal response at 12 months (odds ratio [OR] of response for the EuroLupus regimen, reference NIH regimen: 0.76; 95% confidence interval [CI] 0.29-1.98). There was also no significant association between CYC regimen and achieving at least a partial renal response at 12 months (OR 1.35, 95% CI 0.57-3.19). Our study failed to demonstrate a benefit of the NIH regimen over the EuroLupus CYC regimen in childhood-onset proliferative LN. However, future prospective outcome studies are needed.

Low Erythropoietin to Albumin Ratio in the Serum Predicts Less Reversibility of Renal Impairment with Poorer Prognosis in Multiple Myeloma

Background: Renal impairment (RI) is one of the most common clinical presentations in patients with multiple myeloma (MM) and contributes to its morbidity and mortality. In consistent with this, renal injury is an important factor considered high risk for MM in recently updated NCCN clinical practice guideline. It has been demonstrated that RI is reversible in about half the patients with MM and reversal of renal dysfunction significantly affects the prognosis of MM (Blood Cancer J. 2014 Aug 1;4(8):e235). Because reversibility of RI was a more important prognostic factor than response to anti-myeloma therapy in patients with MM with RI (Clin Lymphoma Myeloma Leuk. 2022 Aug;22(8):626-634; Eur J Haematol. 2000 Sep;65(3):175-81), identification of accurate non-invasive predictive markers for differentiating reversible / irreversible RI in MM patients treated with anti-myeloma therapy is undoubtedly needed. Methods: We conducted a retrospective study to evaluate the predicting value of serum erythropoietin (EPO) to albumin ratio (EPO/albumin) of MM patients treated with anti-myeloma therapy for reversibility of RI and overall survival (OS). RI was defined as an estimated glomerular filtration rate (eGFR) that was measured before treatment ≦50 ml/min per 1.73 m 2 by the simplified Modification of Diet in Renal Disease formula, and the definition of the reversibility of RI were also based on eGFR measurements, as previous publications described (J Clin Oncol. 2010 Nov 20;28(33):4976-84). Renal complete response (CRrenal) was defined as a sustained improvement from an eGFR baseline value of lower than 50 to ≥60 mL/min/1.73 m 2. Partial renal response (PRrenal) was defined as a sustained recovery of eGFR at the time of diagnosis of less than 15 to 30-59 mL/min/1.73 m 2; when achieved CRrenal or PRrenal, the MM patients with RI is defined as the renal responder group, otherwise, the MM patients with RI is defined as the renal non-responder group. Total 52 newly diagnosed MM patients with RI were analyzed in this study, 27 cases in the renal responder group and 25 cases in the renal non-responder group. Bortezomib with high-dose dexamethasone were used as the treatment of choice for such patients. Serum EPO levels were determined using chemiluminescence immunoassay. In our research, mean ± standard deviation (SD) was used to describe the normally distributed variables data while median with interquartile range (IQR) was used to describe the nonparametric variables data. P&amp;lt;0.05 was taken to indicate significance in all analyses. Results: There were significant differences in serum EPO and albumin, hemoglobin and RDW between the renal responder group and the non-responder group. The renal responder group had higher EPO [median: 44.06 (IQR: 160.96) vs 13.58(26.49)] and RDW [median:53(IQR:15) vs 48(9)], lower serum albumin (mean:30.21±SD: 7.78 vs 35.79±6.01) and hemoglobin. (mean:66.56±SD:16.42 vs 78.76±19.79), compared with the non-responder group. Of note, there were no significant differences in serum β2-Microglobulin, creatinine and eGFR at baseline between the two groups. As expected, serum EPO was negatively correlated with serum albumin (r = -0.257, P = 0.033). Likewise, EPO/albumin was negatively correlated with albumin (r = -0.42, P = 0.002); In contrast, EPO/albumin was positively correlated with serum EPO (r = 0.98, P &amp;lt; 0.001). Importantly, our study showed that EPO/albumin were independent predictor of the reversal of RI in MM patients. The optimal cutoff for EPO/albumin was determined via ROC analysis and was determined to be 1.77 U/g. The area under the curve was 0.784. According to the optimal cutoff value, low and high EPO/albumin groups were defined. The data confirmed that the group (n=36) with low EPO/albumin in the serum had shorter OS in MM with RI, compared with the group (n=16) with high EPO/albumin. Conclusions: Our findings demonstrated that low EPO/albumin in the serum predicts less reversibility of RI with poorer prognosis in MM, it is a reliable biomarker for predicting reversibility of RI in MM patients before anti-myeloma therapy. Figure 1

A Phase 2 Study of Isatuximab in Combination with Bortezomib, Cyclophosphamide, and Dexamethasone, Followed By Isatuximab and Lenalidomide Maintenance in Newly Diagnosed Patients with Multiple Myeloma and Severe Renal Impairment

Introduction Renal impairment (RI), a common complication of multiple myeloma (MM), is associated with increased risk of early death. Reversal of MM-associated RI is a key predictor of improved survival. Regimens containing bortezomib and dexamethasone are the treatment backbone for newly diagnosed (ND) patients (pts) with MM and severe RI, even those requiring dialysis. In the ICARIA-MM study, the addition of isatuximab (Isa) to pomalidomide and dexamethasone improved the renal response rate (RRR) in pts with relapsed/refractory MM and RI. We investigated the effect of induction treatment with Isa plus bortezomib, cyclophosphamide, and dexamethasone (VCd) on the renal function of pts with NDMM and severe RI. Additionally, we evaluate the efficacy and safety of IsaVCd induction, followed by Isa and lenalidomide (Len) maintenance. Methods EAE116 (NCT05147493) is an ongoing, investigator-initiated, phase II, prospective, open-label study aiming to enroll ~51 pts in six Greek hospitals. Eligible pts are adults with documented NDMM by International Myeloma Working Group (IMWG) criteria and severe RI (estimated glomerular filtration rate [eGFR] &amp;lt;30 ml/min/1.73m 2) or in need of dialysis. Pts must also have adequate bone marrow and hepatic function and Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2. Excluded are pts with prior/current systemic therapy or stem cell transplantation for any plasma cell dyscrasia, history of malignancy other than MM, meningeal involvement of MM, cardiac disease, hepatitis, ongoing grade (gr) ≥2 peripheral neuropathy, or those with major surgery within two weeks before cycle (Cyc)1, day (D)1. In induction (six 28-day cycles), pts receive: Isa 10 mg/kg IV (Cyc 1: D1, 8, 15, 22; Cyc 2-6: D1, 15); bortezomib 1.3 mg/m 2 SC (Cyc 1: D1, 4, 8, 11; Cyc 2-6: D1, 8, 15, 22); cyclophosphamide 300 mg/m 2 IV (Cyc 1: D1, 8, 15; Cyc 2-6: D1, 8, 15, 22); and dexamethasone 40 mg PO or IV (Cyc 1: D1, 2, 3, 4, 9, 10, 11, 12; Cyc 2-6: D1, 8, 15, 22). In maintenance (Cyc 7 onwards), pts receive Isa 10 mg/kg IV (D1 of each Cyc) and Len 10 mg PO (or adjusted according to renal function) daily (D1-28 of each Cyc). Fifteen to 60 minutes before Isa infusions, pts receive pre-medications to mitigate potential infusion-related reactions. Treatment continues until disease progression, unacceptable toxicity, or consent withdrawal. The study primarily assesses the RRR (proportion of pts with partial renal response or better, using the eGFR cutoff values of the IMWG response criteria) at six months of treatment with IsaVCd. Other study objectives assess the pts' overall response rate (ORR; defined as partial response [PR] or better) and the safety of IsaVCd. Adverse events are classified using the Medical Dictionary for Regulatory Activities. Herein, we present safety and efficacy data for all treated patients (cut-off date 15/05/23. Results Twenty-five pts have been enrolled and have received ≥1 study treatment dose; of these, 20 (80.0%) are continuing with treatment and five (20.0%) have died. At baseline, pts had a median age of 70.0 years (range 46.0-87.0), 18 (72.0%) were male, and 22 (88.0%) had ECOG PS ≤1. Thirteen (52.0%) pts were at stage II and 12 (48.0%) pts at stage III by the revised International Staging System, 6 (24.0%) pts had lytic bone lesions, 5 (20.0%) pts had high-risk cytogenetics, and 5 (20.0%) pts had soft-tissue plasmacytomas. Seven (28.0%) pts were in need of dialysis (Table 1). At a median follow-up of 3.9 months (range 0.1-8.3), pts have received a median of 4.0 treatment cycles (range 1.0-9.0). Eight (32.0%) pts have completed ≥ 6 treatment cycles. RRR was achieved by 5/11 (45.5%) pts who had initiated treatment 6 months before the cutoff date. The median time to RR was 2.8 months (range 0.9-7.0). Of the 19 (76.0%) response evaluable pts, 11 (57.9%) achieved ORR (very good partial response: 6 [31.6%]; PR: 5 [26.3%]). The median time to first response was 1.0 months (range 0.9-1.9). Twenty (80.0%) pts had ≥1 treatment-emergent adverse events (TEAE). Of these, 10 (50.0%) pts had ≥1 gr ≥3 TEAE and 7 (43.8%) pts had ≥1 gr ≥3 serious TEAE. The most common gr ≥3 TEAE was peripheral neuropathy in 5 pts (20.0%) (Table 2). Conclusions Pts with NDMM and severe RI treated with upfront IsaVCd achieve RR consistent with those reported in the literature for pts receiving bortezomib-based therapy, although longer follow-up is needed to assess the regimen's impact on RI. No new safety signals were observed with IsaVCd.

Abstract 15 — Lupus Low Disease Activity State: An Underutilised Clinical Target that is Attainable and Protective against Lupus Nephritis Relapse

Background Lupus nephritis (LN) is a significant comorbidity affecting approximately 50-60% of patients with systemic lupus erythematosus (SLE). Complete and partial renal response (CRR/PRR) have been recommended as treatment targets in LN. Lupus low disease activity state (LLDAS) is also associated with favourable clinical outcomes. This study aims to investigate the LLDAS attainment rate and outcomes in patients with LN. Methods Patients with biopsy-proven LN during 2010-2020 in Queen Mary Hospital were included. Baseline demographics, blood parameters and urinalysis results were documented. Renal response and LLDAS attainment were assessed at 12 months after LN diagnosis. CRR was defined as proteinuria [Formula: see text]0.5g/day with a normal estimated glomerular filtration rate (eGFR); PRR was defined as a reduction in proteinuria by [Formula: see text]50% with near normal eGFR. A relapse was defined as a biopsy-proven active LN on histology after an initial treatment response of proteinuria reduction of [Formula: see text]50% or to sub-nephrotic range. Time-to-relapse survival analysis was performed to compare the significance of CRR/PRR and LLDAS attainment. Results 143 LN patients were included, with a median follow-up duration of 10.4 years. At 12 months, 57 (40%), 14 (10%) and 69 (48%) patients achieved CRR, PRR and LLDAS, respectively. Although 39 (27%) patients attained both CRR/PRR and LLDAS, a significant number of 30 (21%) patients reached LLDAS without meeting CRR/PRR (Figure 1). Among 136 patients who achieved the pre-defined treatment response, 30 (22%) patients developed LN relapse after a median of 2.98 years. Patients reaching either CRR/PRR or LLDAS had a significantly lower risk of relapse (CRR/PRR: HR = 0.34, p = 0.02; LLDAS: HR = 0.28, p = 0.003). The attainment of both CRR/PRR and LLDAS was associated with the lowest risk of relapse (Figure 2). Conclusion We advocate LLDAS as a target for LN patients as attaining LLDAS reduces future LN relapse risks.

Anifrolumab in lupus nephritis: results from second-year extension of a randomised phase II trial

ObjectiveTo characterise the safety and efficacy of anifrolumab in active lupus nephritis (LN) through year 2 of the phase II randomised, double-blind Treatment of Uncontrolled Lupus via the Interferon Pathway...

Efficacy and safety of belimumab therapy for patients with lupus nephritis: A meta-analysis and a propensity score-matched case-control study.

In this study, we performed a meta-analysis and a propensity score-matched case-control study to evaluate the efficacy and safety of belimumab in patients with lupus nephritis(LN). We analyzed the data from three randomized controlled trials (RCTs) to assess the effects of belimumab treatment on renal improvement and adverse effects. Our study included a total of six LN patients who received belimumab treatmentand an additional six LN patients who received standard therapy. All participants were followed up for a duration exceeding 96 weeks to evaluate the outcomes of the treatments. Our meta-analysis incorporated data from three articles involving a total of 666 patients. The results of the analysis revealed that a higher proportion of patients who received belimumab treatment experienced renal improvement compared to those in the control group. The patients in belimumab group had a higher renal complete response rate and proteinuria improvement rate compared to the control group. However, belimumab treatment did not increase the renal partial response rate compared to the control group. The belimumab group also exhibited a higher proportion of patients who achieved normalization of antidouble-stranded DNA, as well as normalization of low C3and C4 levels. In our case-control study, significant improvement in proteinuria was demonstrated with belimumab at Week 48 (p = 0.037) and at all subsequent time points (all p < 0.05). Over the course of 96 weeks, belimumab treatment was associated with renal function stabilization and an increase in C3 and C4 levels. Moreover, the use of belimumab resulted in a reduction in glucocorticoid dosage at Week24 (p = 0.02). Additionally, patients receiving belimumab treatment had a lower risk of severe treatment-emergent adverse events, and no other significant adverse effects were observed between the two groups. In patients with LN, the utilization of belimumab therapy has demonstrated notable improvements in renal response rates. Additionally, it has shown a decreased likelihood of serious treatment-related adverse events and a diminished need for glucocorticoid dosage when compared to the active control group.

#5163 RATIONAL USE OF ECULIZUMAB IN SECONDARY ATYPICAL HAEMOLYTIC UREMIC SYNDROME

Abstract Background and Aims Secondary atypical hemolytic uremic syndrome (secondary aHUS) is a heterogeneous group of thrombotic microangiopathies (TMA) associated with various underlying conditions. Unlike primary aHUS, there is still no hard evidence on the efficacy of complement blockade in treating secondary aHUS since the two main series in the literature that investigate this subject show discrepant results. Our work aims to reassess Eculizumab's efficacy in treating secondary aHUS. Method Observational, retrospective, single-center study, in which we analyzed the hematological and renal evolution of 24 patients diagnosed with secondary aHUS who received treatment with Eculizumab compared with a control cohort of 14 patients who did not receive Eculizumab. Complete renal response was defined as the recovery of renal function before the event, partial renal response as a recovery of 50% of lost glomerular filtration rate, and hematological response as normalization of hemoglobin and platelets. Results We found no statistically significant differences in baseline characteristics or disease severity between both groups. After a median of 5 doses of Eculizumab, the group of patients who received complement blockade presented a significant difference in renal response (complete in 47.8% of patients and partial in 17.4%) compared to the control cohort (complete response 14.3% and partial of 14.3%). Rates of hematological remission were similar in both groups (87% in the eculizumab cohort and 85.7% in the control cohort). Conclusion Rational and early use of Eculizumab in patients with secondary aHUS could be an effective and safe therapeutic option, guaranteeing better renal recovery compared to patients who do not receive complement blockade.

#3032 EFFICACY AND SAFETY OF VOCLOSPORIN IN PATIENTS WITH PROTEINURIA ≥2 MG/MG: AN INTEGRATED ANALYSIS OF THE AURA-LV AND AURORA 1 STUDIES

Abstract Background and Aims Proteinuria has been established as a mediator of progressive renal damage in many nephropathies. However, recent studies of several monoclonal antibodies demonstrated a lack of efficacy in patients with lupus nephritis and moderate to high levels of proteinuria (UPCR ≥2 to ≥3 mg/mg), potentially due to an increase in renal antibody clearance.1-4 Given that, we examined the efficacy and safety of voclosporin in patients with lupus nephritis and a UPCR of ≥2 mg/mg using the pooled dataset from the Phase 2 AURA-LV and Phase 3 AURORA 1 trials. Method Both studies enrolled patients with biopsy-proven LN (Class III, IV, or V ± III/IV, biopsied within 6 months in AURA-LV or up to 2 years in AURORA 1) and proteinuria ≥1.5 mg/mg (≥2 mg/mg for Class V). Patients were randomized to receive either voclosporin (23.7 mg BID) or placebo and treated for up to one year (48 weeks [AURA-LV], 52 weeks [AURORA 1]); all patients received MMF and low-dose steroids. For this post-hoc analysis, changes in UPCR and renal response rates were evaluated in patients with baseline UPCR ≥2 mg/mg. Complete renal response (CRR) was defined as UPCR ≤0.5 mg/mg with stable renal function, low-dose steroids, and no rescue medication; partial renal response (PRR) was defined as a ≥50% reduction in UPCR from baseline. Safety outcomes were also assessed. Results The pooled analysis included 268 and 266 patients in the voclosporin and control arms, respectively. Of those, 217 and 215 patients had UPCR ≥2 mg/mg (baseline mean [SD], 5.2 [3.4] vs. 4.6 [2.9] mg/mg, respectively). A significantly greater percentage of voclosporin-treated patients achieved a CRR at one year compared to the control arm (41.0% vs. 21.9%; odds ratio [OR] 2.48, p&amp;lt;0.0001, Figure 1A). Similarly, significantly more patients in the voclosporin arm (69.6%) than control arm (50.0%) achieved a PRR at the same time point (OR 2.3, p&amp;lt;0.0001); this endpoint was met significantly earlier in voclosporin-treated patients as well (29 vs. 57 days, hazard ratio [HR] 2.0, p&amp;lt;0.0001). The median time to UPCR ≤0.5 mg/mg was also significantly earlier in the voclosporin arm (211 days); less than 50% of the control arm achieved this endpoint within the study period (OR 1.9, p&amp;lt;0.0001, Figure 1B). Adverse event rates were comparable in both arms (Table 1), and mean eGFR levels were similar and stable over the study period, a trend that was maintained for AURORA 1 patients who continued randomized treatment for another two years in the AURORA 2 study. Conclusion Consistent with results from the overall pooled study population, patients with UPCR ≥2 mg/mg at baseline treated with voclosporin achieved significantly higher renal response rates and significantly earlier reductions in UPCR than patients treated with MMF and low-dose steroids alone. These findings are clinically important given the lack of effective therapies available for patients with high baseline proteinuria.

Efficacy and Safety of Belimumab in Lupus Nephritis Patients: A Real-World Observational Study in China

Background: This study aimed to describe disease activity, clinical outcome, and overall patterns of lupus nephritis care in patients who received belimumab in a real-world clinical setting in China. Materials and Methods: This observational cohort study included lupus nephritis patients who received belimumab as adjunct therapy. We deeply investigated the characteristics of those patients including clinical response to belimumab and safety. Results: All 61 lupus nephritis patients were included with a median follow-up period of 9 months (6, 19). Prevalence of proteinuria (52.5–24.6%) and hematuria (33.3–9.8%) was decreased with a stable level of eGFR at last visit. The percentage of patients achieved complete or partial renal response increased from 47.5% to 78.7% and the proportion of complete or partial renal response in patients with proliferative lupus nephritis was higher than those with membranous lupus nephritis (75 vs. 50%) at last visit. The median SLEDAI score decreased from 6 to 2, and there was an increase in patient of LLDAS from 17 to 33 at last visit. A notable dose reduction was seen for glucocorticosteroid dose, with a median change from 10 to 5 mg/d. The proportion of patients receiving >7.5 mg/d steroids reduced from 52.5% at baseline to 23.0% at last visit. The discontinuation of belimumab was rare (3/61) for drug-induced fever, hyperthyroidism, and uveitis. Conclusions: Lupus nephritis patients with belimumab demonstrated improvements in clinical response and a reduction in glucocorticosteroids, which provided evidence of effectiveness and safety in real-world clinical practice in China.

Efficacy of belimumab combined with rituximab in severe systemic lupus erythematosus: study protocol for the phase 3, multicenter, randomized, open-label Synbiose 2 trial

BackgroundBelimumab, an anti-B-cell activating factor antibody, is approved for the treatment of auto-antibody positive systemic lupus erythematosus with a high degree of disease activity. Anti-CD20 B cell depletion with rituximab is used in refractory SLE as well, although with variable responses. We hypothesized that incomplete B cell depletion, related to a surge in BAFF levels following rituximab treatment, can cause ongoing disease activity and flares. The Synbiose 1 study primarily focused on immunological effects and shows the preliminary clinical benefit of combined rituximab and belimumab in SLE. The Synbiose 2 study will evaluate the clinical efficacy of combining belimumab with rituximab in patients with severe SLE, allowing the tapering of prednisolone and mycophenolate.MethodsSynbiose 2 is a phase 3, multicenter, randomized, controlled, open-label 2-year clinical trial. Seventy adults with severe SLE including lupus nephritis will be randomized 1:1 to receive either standard of care consisting of prednisolone and mycophenolate as induction and maintenance treatment, or belimumab and rituximab combined with standard of care as induction treatment, followed by prednisolone and belimumab as maintenance treatment. The primary objective is to assess whether combined B cell therapy will lead to a reduction of treatment failure. Secondary endpoints are complete and partial clinical and renal response and the improvement of SLE-specific autoimmune phenomena. Safety endpoints include the incidence of adverse events, with a special interest in infections.DiscussionThe Synbiose 2 trial is the first multicenter phase 3 clinical trial investigating combined B cell targeted therapy in SLE, including lupus nephritis. The outcome of this study will provide further evidence for the clinical efficacy of this new treatment strategy in severe SLE.Trial registrationClinicalTrials.gov NCT03747159. Registered on 20 November 2018.