Complete Renal Response Rate Research Articles

#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 (< 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.

Risk factors for acute kidney injury and kidney relapse in patients with lupus podocytopathy.

Patients with lupus podocytopathy show a high incidence of acute kidney injury (AKI) and relapse, but the risk factors and mechanisms were unclear. This study analysed the clinicopathological features and risk factors for AKI and relapse in lupus podocytopathy patients. The cohort of lupus podocytopathy was generated by screening the biopsies of patients with lupus nephritis (LN) from 2002 to 2022 and was divided into the mild glomerular lesion (MGL) and focal segmental glomerulosclerosis (FSGS) groups based on glomerular morphological characteristics. The acute (ATI) and chronic (CTI) tubulointerstitial lesions were semi-quantitatively scored. Logistic and Cox regressions were employed to identify the risk factors for AKI and relapse, respectively. Among 6052 LN cases, 98 (1.6%) were diagnosed as lupus podocytopathy, with 71 in the MGL group and 27 in the FSGS group. All patients presented with nephrotic syndrome and 33 (34.7%) of them had AKI. Seventy-seven (78.6%) patients achieved complete renal response (CRR) within 12weeks of induction treatment, in which there was no difference in the CRR rate between glucocorticoid monotherapy and combination therapy with glucocorticoids plus immunosuppressants. Compared with the MGL group, patients in the FSGS group had significantly higher incidences of hypertension and haematuria; in addition, they had higher Systemic Lupus Erythematosus Disease Activity Index 2000, ATI and CTI scores but a significantly lower CRR rate. Urinary protein ≥7.0g/24h and serum C3 ≤0.750g/l were independent risk factors for AKI. During a median follow-up of 78months, 57 cases (60.0%) had relapse and none reached the kidney endpoint. Failure to achieve CRR within 12weeks, maintenance with glucocorticoid monotherapy and AKI at onset were independent risk factors for kidney relapse. In this study, histological subtypes of lupus podocytopathy were found to be associated with clinical features and treatment response. In addition, several risk factors associated with AKI occurrence and kidney relapse were identified.

Mycophenolate mofetil vs. cyclophosphamide-based induction regimens for lupus nephritis: Outcomes at a tertiary care centre in Lahore, Pakistan.

To compare the efficacy of mycophenolate mofetil with intravenous cyclophosphamideas induction therapy in lupus nephritis. The observational, prospecrive, cohort study was conducted at the Rheumatology Department of Fatima Memorial Hospital, Lahore, Pakistan, from July 2016 to June 2019, and comprised lupus nephritis patients. For induction therapy, the patients were assigned at the discretion of the treating rheumatologist to mycophenolate mofetil group MMF, and intravenous cyclophosphamide group CYC. The latter group was further divided into NIH subgroup that received the therapy as per the protocol of the National Institutes of Health, and ELNT subgroup which recived the therapy as per the Euro Lupus Nephritis Trial protocol. Maintenance therapy in all groups was mycophenolate mofetil. Tacrolimus was added in case of non-response. The outcome was the achievement of complete renal response at 6, 12 and 24 months. Data was analysed using SPSS 26. Of the 131 patients, 126(96.2%) were females. The overall mean age was 27±7.7 years. There were 58(44.2%) patients in group MMF and 73(55.7%) in group CYC, which had subgroup NIH 46(63%) and subgrpup ELNT 27(37%). The complete renal response rates at 6, 12, and 24 months were 22 (43.1%), 35 (71.4%), and 40(83.3%) for group MMF; 5(12.5%), 9(22%) and 24 (58.5%) for subgroup NIH, and 6(26.1%), 8(36.4%) and 14(63.6%) for subgroup ELNT. Group MMF outcomes were significantly better than the rest (p<0.05). Mycophenolate mofetil induction therapy was more effective than intraveenous cyclophosphamide in terms of achieving remission at 6, 12 and 24 months.

Safety and Efficacy of New Drugs Combinations in Newly Diagnosed Multiple Myeloma with Renal Failure at Onset: A Retrospective Multicentric Study

Renal injury at onset of newly diagnosed multiple myeloma (NDMM) is associated with poor outcome. Patients with severe renal failure due to MM are excluded from clinical trials with new drugs. The aim of this retrospective study was to describe the clinical characteristics, the treatment choices, the efficacy and the incidence of treatment-related toxicities of NDMM patients with renal insufficiency. We enrolled all NDMM patients with renal failure due to the disease treated at our Centers from 2012 to present. Fifty-one patients with a median age of 75 years were included; 76% had an International Staging System (ISS) of 3; 76% had anemia, 74% bone lesions and 30% had hypercalcemia; 31% had micromolecular myeloma. Thirty seven percent of patients had severe renal failure requiring dialysis treatment. Thirty-five percent of patients received treatment according to a VMP (Bortezomib, Melphalan and Prednisone) scheme, 20% received a triplet including Bortezomib and an immunomodulatory drugs (IMIDs) and 33% received a regimen including Daratumumab. The remaining 12% received a douplet (lenalidomide-dexamethasone or melphalan-prednisone). Thirty one percent of patients underwent an autograft procedure. Overall response rate (ORR) was 94% with a complete response (CR) rate of 17%. In terms of recovery of renal function, 50% achieved at least minimal renal response according to IMWG criteria, with 40% obtain a complete recovery of renal function. Patients who received more innovative treatment (regimens containing Daratumumab or Bortezomib in combination with IMIDs) achieved a response rate superior than very good partial response (≥ VGPR) of 74% with hematologic, neurologic, and infectious toxicities grade ≥ 3 of 22%, 7%, and 26%, respectively. Patients who received therapy with VMP or douplet had response rates ≥ VGPR of 25% with hematologic, neurologic, and infectious toxicity grade ≥ 3 rates of 29%, 4%, and 21%, respectively. Complete renal response rates in these two groups of patients were 45% and 20%, respectively. No death due to toxicity was registered. Patients with NDMM with renal failure at onset had a high burden of disease with unfavorable prognostic features. Although the small numbers of the cohort and the retrospective nature of this study it can be concluded that these patients can received new drugs combinations treatments with excellent response rates and without increased toxicity.

Effects of Belimumab (BEL) on Renal Outcomes in Patients (pts) With Relapsed and Newly Diagnosed Active Lupus Nephritis (LN)

Despite standard therapy (ST) for LN, only 20–40% of pts achieve complete renal response (CRR) at 0.5–1 year and 20–25% relapse in 3–5 years. The aim of this study was to assess effects of BEL on renal outcomes in relapsed and newly diagnosed pts with LN. Post hoc analysis of the Phase 3, randomized, double-blind, 104-week BLISS-LN study (GSK BEL114054; NCT01639339). Pts with active LN received monthly intravenous (IV) BEL 10 mg/kg or placebo (PBO) + ST. Randomization was stratified by induction regimen: high dose corticosteroids (HDCS) + cyclophosphamide (CYC), followed by azathioprine + low-dose corticosteroids (LDCS), or HDCS + mycophenolate mofetil (MMF), followed by MMF + LDCS. We assessed primary efficacy renal response (PERR; uPCR ≤0.7; eGFR no more than 20% below pre-flare value or ≥60 ml/min/1.73m2; no rescue therapy) and CRR (uPCR <0.5; eGFR no more than 10% below pre-flare value or ≥90 ml/min/1.73m2; no rescue therapy) at Week 104 and time to renal-related event or death in relapsed vs newly diagnosed pts. Of 446 pts included in this analysis, 150 had relapse of LN and 296 were newly diagnosed. Positive effects of BEL vs PBO on PERR and CRR were noted in both subgroups and were numerically greater in relapsed vs newly diagnosed pts (Table). BEL-treated pts had a lower risk at any time of experiencing a renal-related event or death vs PBO in both subgroups ( Table 1 ). These data suggest BEL improved PERR and CRR rates more potently in relapsed pts, in which PERR and CRR were substantially less frequent compared with newly diagnosed LN.

Differences and similarities of proliferative and non-proliferative forms of biopsy-proven lupus nephritis: Single centre, cross-disciplinary experience.

ObjectiveWe aimed to compare clinical features, outcomes, treatments, and to define the predictive factors of complete renal response (CRR) in patients with proliferative and non-proliferative lupus nephritis (LN).MethodsPatients with systemic lupus erythematosus (SLE) followed between 2014 and 2020 at Hacettepe University Hospitals and who had a kidney biopsy were the subject of the study. One hundered and sixteen patients’ kidney biopsies reported as LN were evaluated retrospectively. Clinical characteristics and laboratory values at the time of kidney biopsy, histopathological forms of LN, and renal response (complete or partial) were recorded. We analyzed the association between CRR rates during the 2-year follow-up after induction therapy and the predictive factors for CRR.ResultsOf 116 (93 females, 23 males) patients, 95 (81.9%) were in the proliferative group (class III and IV) and 21 (18.1%) were in the non-proliferative group (class II and V). In the proliferative group, the percentage of the patients with elevated basal creatinine levels, median daily proteinuria, anti-double-stranded DNA (dsDNA) positivity, low C3 and C4 levels, the presence of active urinary sediment, and median renal SLE Disease Activity Index (SLEDAI) scores at the time of kidney biopsy were significantly higher than the non-proliferative group. Renal response status during the 2-year follow-up after induction therapy was available for 99 patients. During this time, 70 (70.7%) patients had achieved CRR and time-to-CRR was similar between the proliferative and non-proliferative groups (p = 0.64, log-rank test). The Cox proportional hazards model showed that achievement of CRR was associated with female gender [HR: 2.15 (1.19–3.89 95% CI), p = 0.011], newly diagnosed SLE with renal biopsy [HR: 2.15 (1.26–3.67 95% CI), p = 0.005], hypertension [HR: 0.40 (0.27–0.94 95% CI), p = 0.032], eGFR increase [HR: 1.01 (1.00–1.01 95% CI), p = 0.046], and the presence of active urinary sediment [HR: 0.46 (0.22–0.96 95% CI), p = 0.039].ConclusionsAchieving CRR was similar in proliferative and non-proliferative LN patients, although certain laboratory parameters differed at the onset. Our results indicated the importance of kidney biopsy in the decision-making of treatment of SLE patients with renal involvement and that the defined factors associated with CRR achievement help to predict good renal response.

Medium Versus High Initial Prednisone Dose for Remission Induction in Lupus Nephritis: A Propensity Score-Matched Analysis.

The existing guidelines for lupus nephritis (LN) recommend initial prednisone doses of 0.3-1.0 mg/kg/day. However, recent studies reported noninferior outcomes with lower doses. The aim of this study was to compare the complete renal response rates in LN patients treated with prednisone ≤30 mg/day or ≥40 mg/day. Patients with new-onset LN and standard immunosuppressive treatment were followed for at least 12 months, divided into medium (≤30 mg/day) and high prednisone groups (≥40 mg/day) and matched (propensity score) based on the baseline differences. Complete renal response was defined as proteinuria <0.5 gm/day and no worsening in renal function. Glucocorticoid-related damage was also assessed. High-dose prednisone patients (n = 103; mean ± SD dose 48.6 ± 12.3 mg/day) achieved better rates of complete response compared to the medium group (n = 103; mean ± SD dose 24.2 ± 4.6 mg/day) (61.8% versus 38.2%; P = 0.024) at 12 months. The difference in response rates was reproduced for several subgroups (concomitant immunosuppressive treatment, proliferative/nonproliferative LN). Complete remission rates were higher at 2 years (67.8% versus 39%; P = 0.002) and 3 years (64.9% versus 49.1%; P = 0.025) after LN diagnosis. Cumulative glucocorticoid dose was comparable at 2 and 3 years. Glucocorticoid-related damage was accelerated in both groups for the same period. Higher initial prednisone doses (median 45 mg/day) achieved significantly better rates of complete renal response at 12 months in new-onset LN. Cumulative glucocorticoid dose and damage accrual were not different at 2 and 3 years after LN. Damage was more prominent in the late phases of LN in both groups, underlining the importance of rapid tapering and the need to implement alternative strategies.

Voclosporin: a novel calcineurin inhibitor for the treatment of lupus nephritis

ABSTRACT Introduction Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus. Standard-of-care immunosuppressive therapies achieve poor complete renal response (CRR) rates, with considerable toxicity. This article reviews voclosporin, a novel oral calcineurin inhibitor (CNI) approved for treatment in adults with active LN by the US Food and Drug Administration (the FDA) in January 2021. Areas covered This review summarizes the chemical properties, pharmacokinetics, and pharmacodynamics of voclosporin, and its efficacy and safety in LN, based on literature review covering PubMed searches, manufacturers’ websites, and documents produced by the FDA. Expert opinion Voclosporin is a CNI with a consistent pharmacokinetic–pharmacodynamic relationship resulting from enhanced calcineurin binding and reduced drug and metabolite load. This profile permits therapeutic efficacy in LN at a dose associated with relatively low calcineurin inhibition, and therefore a potentially improved safety profile. Pivotal trials demonstrated a significant benefit of adding voclosporin to standard therapy, with rapid reduction in proteinuria, and a clinically meaningful and significantly higher CRR rate at 1 year. At approved doses for LN, potential advantages of voclosporin versus historical experience with CNIs include lack of need for therapeutic drug monitoring, benign metabolic, lipid and electrolyte profile, and no impact on mycophenolate mofetil levels.

POS-390 ELECTROLYTE PROFILES OF LUPUS NEPHRITIS PATIENTS TREATED WITH THE NOVEL CALCINEURIN INHIBITOR VOCLOSPORIN

Electrolyte imbalances, which can be modulated within the kidney, have been previously reported with calcineurin inhibitor (CNI) utilization in solid organ transplant.1,2Dietary supplementation of electrolytes may correct serum electrolyte imbalances; therefore, it can be useful to evaluate urinary excretion over time to detect changes in electrolytes due to diet or to confirm clinical findings in serum. Voclosporin is a novel CNI approved in the US for the treatment of adult patients with active lupus nephritis in combination with background immunosuppressive therapy. Data from the pivotal Phase 3 AURORA 1 study showed that the addition of voclosporin to mycophenolate mofetil (MMF) and low-dose steroids results in higher complete renal response rates at one year (40.8% vs 22.5%; OR 2.65; p<0.0001) in patients with lupus nephritis. AURORA 1 was a double-blind, randomized controlled trial designed to evaluate oral voclosporin (23.7 mg twice daily) compared to placebo in patients with active lupus nephritis, with all patients receiving MMF (target dose 1 g twice daily) and low-dose oral steroids (rapidly tapered to 2.5 mg daily at week 16). Serum electrolyte imbalances including hypomagnesemia are common adverse events associated with CNIs. In contrast to these reports, mean serum electrolyte concentrations of patients treated with voclosporin were within normal ranges in AURORA 1. As serum electrolytes concentrations can be impacted by dietary supplementation, we evaluated urinary excretion rates to assess if inadvertent dietary supplementation during the study had impacted the findings in serum. Twenty-four-hour urine samples from 60 patients in each treatment arm were selected including patients that responded to treatment at one year with at least 50% reduction in urine protein creatinine ratio (UPCR) from baseline (treatment responders), those who had not (non-responders), and patients who had at least 30% reduction from baseline in estimated glomerular filtration rate (eGFR) during the study. Mean change from baseline to one year in magnesium, potassium and sodium are presented as 24-hour urinary electrolyte excretion rates. Mean changes from baseline in urinary electrolyte excretion were small for magnesium (≤13.4 mg/24 hours) and potassium (≤6.4 mmol/24 hours) with no significant differences between treatment arms for any of the subgroups. Sodium excretion decreased from baseline in all subgroups (≤30.5 mmol/24 hours) except for responders in the control arm (increase of 14.0 mmol/24 hours) at one year (Table 1). Patients with lupus nephritis in AURORA 1 treated with voclosporin in combination with MMF and low-dose steroids achieved significantly higher complete renal response rates compared to patients treated with only MMF and low-dose steroids. At the doses studied, changes from baseline in urinary electrolyte excretion of magnesium, potassium, and sodium were not clinically meaningful in either treatment arm regardless of response to treatment. These results confirmed dietary supplementation did not impact the findings in serum concentrations. Together with the reported normal electrolyte concentrations in serum, this study confirms voclosporin has no meaningful impact on mean concentrations of electrolytes. This analysis further supports the safety and efficacy of voclosporin for the treatment of patients with lupus nephritis.

Voclosporin in lupus nephritis: a profile of its use

Voclosporin (Lupkynis™), a novel calcineurin inhibitor, is approved in the USA as an add-on to background immunosuppressive therapy in adults with active lupus nephritis. Voclosporin, in combination with mycophenolate mofetil and low-dose corticosteroids, achieved higher complete renal response rates in adults with active lupus nephritis than mycophenolate mofetil and low-dose corticosteroids alone. Voclosporin treatment led to early and sustained reductions in proteinuria. Voclosporin was generally well tolerated, with no unexpected adverse events.

Journal Club: Efficacy and Safety of Voclosporin Versus Placebo for Lupus Nephritis (AURORA 1): A Double-Blind, Randomized, Multicenter, Placebo-Controlled, Phase 3 Trial.

ObjectiveVoclosporin, a novel calcineurin inhibitor approved for the treatment of adults with lupus nephritis (LN), improved complete renal response rates in patients with LN in a phase 2 trial. This study aimed to evaluate the efficacy and safety of voclosporin for the treatment of LN.MethodsThis multicenter, double‐blind, randomized phase 3 trial was done in 142 hospitals and clinics across 27 countries. Patients with a diagnosis of systemic lupus erythematosus and LN, according to the American College of Rheumatology criteria, who had undergone a kidney biopsy within 2 years that showed class III, IV, or V (alone or in combination with class III or IV) were eligible for this study. Patients were randomly assigned (1:1) to receive oral voclosporin (23.7 mg twice daily) or a placebo, on a background of mycophenolate mofetil (1 g twice daily) and rapidly tapered low‐dose oral steroids, by use of an interactive web response system. The primary endpoint was complete renal response at 52 weeks, defined as a composite of urine protein creatinine ratio of 0.5 mg/mg or less, stable renal function (defined as estimated glomerular filtration rate [eGFR] ≥60 ml/min/1.73m2 or no confirmed decrease from baseline in eGFR of > 20%), no administration of rescue medication, and no more than 10 mg prednisone equivalent per day for 3 or more consecutive days or 7 or more days during Week 44 through Week 52 (just before the primary endpoint assessment). Safety was also assessed. Efficacy analysis was by intention to treat, and safety analysis was by randomized patients receiving at least one dose of study treatment.ResultsBetween April 13, 2017, and October 10, 2019, 179 patients were assigned to the voclosporin group and 178 were assigned to the placebo group. The primary endpoint of complete renal response at Week 52 was achieved in significantly more patients in the voclosporin group than in the placebo group (73 [41%] of 179 patients vs 40 [23%] of 178 patients; odds ratio, 2.65; 95% confidence interval [CI] 1.64‐4.27; P < 0·0001). The adverse event profile was balanced between the two groups; serious adverse events occurred in 37 (21%) of 178 patients in the voclosporin group and 38 (21%) of 178 patients in the placebo group. The most frequent serious adverse event involving infection was pneumonia, occurring in seven (4%) patients in the voclosporin group and in eight (4%) patients in the placebo group. A total of six patients died during the study or study follow‐up period (one [<1%] patient in the voclosporin group and five [3%] patients in the placebo group). None of the events leading to death were considered by the investigators to be related to the study treatments.ConclusionVoclosporin in combination with mycophenolate mofetil (MMF) and low‐dose steroids led to a clinically and statistically superior complete renal response rate versus MMF and low‐dose steroids alone, with a comparable safety profile. This finding is an important advancement in the treatment of patients with active LN.

Superior Efficacy of Carfilzomib and Dexamethasone (Kd56) Vs Bortezomib and Dexamethasone (Vd) in Multiple Myeloma (MM) Patients with Moderate or Serious Renal Failure: A Subgroup Analysis of the Phase 3 Endeavor Study

Abstract Background: Carfilzomib, a second generation selective proteasome inhibitor, is approved in the United States and other countries for the treatment of relapsed or refractory multiple myeloma (RRMM). In the randomized, phase 3 study ENDEAVOR, Kd56 demonstrated clinically and statistically significant improvement compared with Vd in both progression-free survival (PFS) (median 18.7 vs 9.4 months [mos]; hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.44-0.65; 1-sided P Methods: Adults with RRMM (1-3 prior regimens) and creatinine clearance (CrCL) ≥15 mL/min were eligible for the ENDEAVOR trial. The Cockcroft-Gault formula was used to calculate baseline, and on study, renal function. In the Kd56 arm, pts received carfilzomib (30-min intravenous [IV] infusion) on days (D) 1, 2, 8, 9, 15, and 16 (20 mg/m2 on D1, 2 [cycle 1]; 56 mg/m2 thereafter) and dexamethasone (20 mg) on D1, 2, 8, 9, 15, 16, 22, and 23 of 28-day cycles. Pts in the Vd arm received bortezomib (1.3 mg/m2; IV or subcutaneously) on D1, 4, 8, and 11 and dexamethasone (20 mg) on D1, 2, 4, 5, 8, 9, 11, and 12 of 21-day cycles. Pts were treated until disease progression, physician decision, unacceptable toxicity, withdrawal of consent, or mortality. The primary end point was PFS; secondary end points included OS, overall response rate (ORR), duration of response, rate of grade ≥2 peripheral neuropathy (PN), and safety. The present analyses examined efficacy and safety outcomes in pts grouped according to baseline renal function (CrCL ≥15 to Results: A total of 929 pts were enrolled (CrCL ≥15 to Conclusions: To our knowledge, ENDEAVOR is the largest randomized trial in RRMM to have included pts with severe renal impairment. Superior efficacy for Kd56 vs Vd was observed across all renal subgroups. The safety profile was consistent with the findings from the previous interim analysis. Overall, these data suggest that Kd56 has a favorable benefit-risk profile and should be considered as the new standard of care in pts with RRMM, regardless of baseline renal function. Download : Download high-res image (203KB) Download : Download full-size image Disclosures Dimopoulos: Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology: Consultancy, Honoraria, Other: Advisory Committee: Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology; Genesis Pharma: Research Funding; Novartis: Consultancy, Honoraria. Siegel: Celgene, Takeda, Amgen Inc, Novartis and BMS: Consultancy, Speakers Bureau; Merck: Consultancy. White: Bristol-Myers Squibb: Consultancy, Honoraria; Amgen, Celgene, Janssen, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Boccia: Pfizer Inc., Sandoz: Other: Advisory Board. Yang: Amgen Inc.: Employment, Equity Ownership. Kimball: Amgen: Employment, Equity Ownership. Iskander: Amgen: Employment, Equity Ownership. Mezzi: Amgen, Inc.: Employment, Equity Ownership. Ludwig: Janssen-Cilag: Consultancy, Speakers Bureau; Bristol-Meyers: Speakers Bureau; AMGEN: Consultancy, Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau. Niesvizky: Amgen: Consultancy; Celgene: Consultancy; BMS: Consultancy; Janssen: Consultancy.

Efficacy and safety of voclosporin versus placebo for lupus nephritis (AURORA 1): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial

Voclosporin, a novel calcineurin inhibitor approved for the treatment of adults with lupus nephritis, improved complete renal response rates in patients with lupus nephritis in a phase 2 trial. This study aimed to evaluate the efficacy and safety of voclosporin for the treatment of lupus nephritis. This multicentre, double-blind, randomised phase 3 trial was done in 142 hospitals and clinics across 27 countries. Patients with a diagnosis of systemic lupus erythematosus with lupus nephritis according to the American College of Rheumatology criteria, and a kidney biopsy within 2 years that showed class III, IV, or V (alone or in combination with class III or IV) were eligible. Patients were randomly assigned (1:1) to oral voclosporin (23·7 mg twice daily) or placebo, on a background of mycophenolate mofetil (1 g twice daily) and rapidly tapered low-dose oral steroids, by use of an interactive web response system. The primary endpoint was complete renal response at 52 weeks defined as a composite of urine protein creatinine ratio of 0·5 mg/mg or less, stable renal function (defined as estimated glomerular filtration rate [eGFR] ≥60 mL/min/1·73 m2 or no confirmed decrease from baseline in eGFR of >20%), no administration of rescue medication, and no more than 10 mg prednisone equivalent per day for 3 or more consecutive days or for 7 or more days during weeks 44 through 52, just before the primary endpoint assessment. Safety was also assessed. Efficacy analysis was by intention-to-treat and safety analysis by randomised patients receiving at least one dose of study treatment. The trial is registered with ClinicalTrials.gov, NCT03021499. Between April 13, 2017, and Oct 10, 2019, 179 patients were assigned to the voclosporin group and 178 to the placebo group. The primary endpoint of complete renal response at week 52 was achieved in significantly more patients in the voclosporin group than in the placebo group (73 [41%] of 179 patients vs 40 [23%] of 178 patients; odds ratio 2·65; 95% CI 1·64-4·27; p<0·0001). The adverse event profile was balanced between the two groups; serious adverse events occurred in 37 (21%) of 178 in the voclosporin group and 38 (21%) of 178 patients in the placebo group. The most frequent serious adverse event involving infection was pneumonia, occurring in 7 (4%) patients in the voclosporin group and in 8 (4%) patients in the placebo group. A total of six patients died during the study or study follow-up period (one [<1%] patient in the voclosporin group and five [3%] patients in the placebo group). None of the events leading to death were considered by the investigators to be related to the study treatments. Voclosporin in combination with MMF and low-dose steroids led to a clinically and statistically superior complete renal response rate versus MMF and low-dose steroids alone, with a comparable safety profile. This finding is an important advancement in the treatment of patients with active lupus nephritis. Aurinia Pharmaceuticals.

Long-term outcome of a randomised controlled trial comparing tacrolimus with mycophenolate mofetil as induction therapy for active lupus nephritis

ObjectivesTo report the 10-year outcome of lupus nephritis (LN) treated with mycophenolate mofetil (MMF) or tacrolimus (TAC) induction in a randomised controlled trial.MethodsPatients with active LN were treated with MMF...

Isatuximab plus pomalidomide and dexamethasone in relapsed/refractory multiple myeloma patients with renal impairment: ICARIA-MM subgroup analysis

The randomized, phase 3 ICARIA-MM study investigated isatuximab (Isa) with pomalidomide and dexamethasone (Pd) versus Pd in patients with relapsed/refractory multiple myeloma and ≥2 prior lines. This prespecified subgroup analysis examined efficacy in patients with renal impairment (RI; estimated glomerular filtration rate <60 mL/min/1.73 m²). Isa 10 mg/kg was given intravenously once weekly in cycle 1, and every 2 weeks in subsequent 28-day cycles. Patients received standard doses of Pd. Median progression-free survival (PFS) for patients with RI was 9.5 months with Isa-Pd (n = 55) and 3.7 months with Pd (n = 49; hazard ratio [HR] 0.50; 95% confidence interval [CI], 0.30–0.85). Without RI, median PFS was 12.7 months with Isa-Pd (n = 87) and 7.9 months with Pd (n = 96; HR 0.58; 95% CI, 0.38–0.88). The overall response rate (ORR) with and without RI was higher with Isa-Pd (56 and 68%) than Pd (25 and 43%). Complete renal response rates were 71.9% (23/32) with Isa-Pd and 38.1% (8/21) with Pd; these lasted ≥60 days in 31.3% (10/32) and 19.0% (4/21) of patients, respectively. Isa pharmacokinetics were comparable between the subgroups, suggesting no need for dose adjustment in patients with RI. In summary, the addition of Isa to Pd improved PFS, ORR and renal response rates.

Impact of stringent response in proteinuria on long-term renal outcomes in proliferative lupus nephritis.

Favourable long-term prognosis in proliferative lupus nephritis (LN) is associated with the achievement of complete renal response (CR), which is defined as a urine protein/creatinine ratio (UPCR) of < 0.5. However, it is unclear whether a more stringent cut-off for proteinuria (normal value of proteinuria; UPCR < 0.15) is better than CR. We aimed to evaluate the effect of stringent CR, defined as a UPCR of <0.15, on long-term renal outcomes in proliferative LN. We included 87 patients with class III or IV LN who achieved CR at one year after induction therapy. Clinical and laboratory data were compared between the stringent and non-stringent CR groups. Logistic regression analysis was performed to identify factors associated with achievement of stringent CR. Cox analysis was performed to analyse the risk factors for renal flare and development of chronic kidney disease (CKD). The stringent and non-stringent CR groups included 58 and 29 patients, respectively. The two groups showed no significant baseline differences in terms of the clinical, laboratory and pathological classification. The sustained CR rates during five years were 91.3% and 50.0% (p = 0.014) in the stringent and non-stringent CR groups, respectively. In Cox analyses, the achievement of stringent CR was associated with a lower risk of five-year renal flare rate (hazard ratio (HR) = 0.161, 95% confidence interval (CI) 0.063-0.411, p < 0.01) and development of CKD (HR = 0.189, 95% CI 0.047-0.752, p = 0.018). Mycophenolate mofetil induction therapy was associated with achievement of stringent CR at a borderline level of significance (HR = 7.268, 95% CI 0.894-59.089, p = 0.064). Achievement of stringent CR predicted lower risk of renal flare and development of CKD in proliferative LN. These findings suggest that stringent CR is a valuable treatment target in proliferative LN.

High plasma mycophenolate acid concentration in the early phase of induction therapy predicts good renal outcome in lupus nephritis

Objectives: To identify the prognostic predictive factor of complete renal response (CR) at week 12 by focusing on the plasma mycophenolic acid (MPA) concentration in induction therapy in lupus nephritis.Methods: We prospectively enrolled patients with biopsy-proven LN class III/IV who were hospitalized between 2016 and 2017. As an induction therapy, mycophenolate mofetil was continuously introduced at 2000 mg/day. We measured the MPA plasma concentration at two time points depending on the induction therapy phase, early (week 4) or middle (week 12). The association between these concentrations and CR rate at week 12 was evaluated.Results: Ten patients were enrolled. A significantly higher AUC0–12 between 0 and 12 h of MPA at the early phase was observed in the patients with CR at week 12 than in those without (p = .03). All the patients with high MPA-AUC0–12 (> 40 mg h/L) at the early phase achieved CR at week 12, but no such association was found at the middle phase. The multivariate analysis revealed that MPA-AUC0–12 was selected as an independent predictive factor of CR at week 12 (odds ratio: 1.12; 95% confidence interval: 1.01–1.45, p = .02).Conclusion: The high AUC0–12 of MPA at the early phase of induction therapy may predict good renal response.

Factors predictive of long-term mortality in lupus nephritis: a multicenter retrospective study of a Japanese cohort.

Lupus nephritis (LN) is a major determinant of mortality in systemic lupus erythematosus (SLE). Here we evaluated the association between complete renal response (CR) and mortality in LN. We retrospectively analyzed the cases of 172 of 201 patients with LN for whom data on the therapeutic response at 6 and 12 months after induction therapy were available. The patients underwent a renal biopsy at Nagasaki University Hospital and community hospitals in Nagasaki between the years 1990 and 2016. We determined the CR rates at 6 and 12 months after induction therapy initiation and evaluated the predictive factors for CR and their relationship with mortality. We performed univariate and multivariable competing risks regression analyses to determine the factors predictive of CR. The patients' survival data were analyzed by the Kaplan-Meier method with a log-rank test. The median follow-up duration after renal biopsy was 120 months (interquartile range: 60.3-191.8 months). The 5-, 10-, 15- and 20-year survival rates of our cohort were 99.3, 94.6, 92.0 and 85.4%, respectively. During follow-up, nine patients (5.2%) died from cardiovascular events, infection, malignancy and other causes. The multivariate analysis revealed that the following factors were predictive of CR. At 6 months: male gender (odds ratio (OR) 0.23, 95% confidence interval (CI) 0.08-0.65, p = 0.0028), proteinuria (g/gCr) (OR 0.83, 95% CI 0.71-0.97, p = 0.0098) and index of activity (0-24) (OR 0.84, 95% CI 0.71-0.99, p = 0.0382). At 12 months: male gender (OR 0.25, 95% CI 0.09-0.67, p = 0.0043) and index of activity (0-24) (OR 0.82, 95% CI 0.69-0.98, p = 0.0236). The Kaplan-Meier analysis showed that compared to not achieving CR at 12 months, achieving CR at 12 months was significantly correlated with the survival rate (OR 0.18, 95% CI 0.04-0.92, p = 0.0339). Our results suggest that the survival rate of patients with LN is associated with the achievement of CR at 12 months after induction therapy, and that male gender and a higher index of activity (0-24) are the common predictive factors for failure to achieve CR at 6 and 12 months.

A positive direct Coombs' test in the absence of hemolytic anemia predicts high disease activity and poor renal response in systemic lupus erythematosus.

We determined the clinical utility of the direct Coombs' test in the absence of hemolytic anemia as an indicator of disease activity and therapeutic response in systemic lupus erythematosus (SLE). SLE patients without hemolytic anemia who visited our hospital from January 2016 to November 2016 were retrospectively evaluated with a direct Coombs' test. Clinical features, including SLE disease activity index (SLEDAI), treatment and laboratory findings were analyzed. For patients with lupus nephritis, we additionally evaluated the cumulative complete renal response rate over one year after induction therapy. Among 182 patients evaluated, 10 (5.8%) patients had a positive direct Coombs' test in the absence of hemolytic anemia. They had a higher SLEDAI ( p < 0.01), higher circulating immune complex levels ( p = 0.01), higher anti-DNA titers ( p < 0.01) and a lower complete renal response rate ( p = 0.03) compared with those who were negative. Multivariate analysis indicated that SLEDAI was an independent factor correlated with the direct Coombs' test without hemolytic anemia (odds ratio 2.4, 95% confidence interval 1.66-4.98, p < 0.01). A positive direct Coombs' test in the absence of hemolytic anemia may therefore represent a useful biomarker for assessing disease activity and therapeutic response.

Lack of partial renal response by 12\xa0weeks after induction therapy predicts poor renal response and systemic damage accrual in lupus nephritis class III or IV

BackgroundLupus nephritis class III or IV is associated with a poor prognosis for both patient and renal survival. Recommendations for the management of lupus nephritis have recently been established, and changing therapies is recommended for patients who do not respond adequately to induction therapy. However, it remains a major challenge to determine when to switch the treatment. In this study, we identified early prognostic factors capable of predicting poor renal outcome as well as overall damage accrual in patients with lupus nephritis class III or IV.MethodsEighty patients with biopsy-proven lupus nephritis class III or IV were retrospectively recruited and divided into two groups: those with complete renal response (CR) or non-CR at 3 years after induction therapy. We investigated when clinical responses were obtained at each observational period from baseline to year 3. Clinical responses were divided into three groups: CR, partial renal response (PR), and non-PR. Furthermore, patients were assessed using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) and cumulative dose of corticosteroid for 3 years.ResultsForty-four patients with CR and thirty-six with non-CR were enrolled. The cumulative CR rate was 85.0%. PR rates of patients with CR were significantly higher than those with non-CR from week 12 (p < 0.01). We identified the achievement of PR at 12 weeks as an independent predictor (OR 3.57, p = 0.03) by multivariate analysis. We next divided all patients into two groups according to PR achievement at week 12. The cumulative CR rate of the patients who achieved PR at week 12 was significantly higher than that of those who did not (96.5% vs 69.2%, p < 0.001). Furthermore, a significantly higher SDI and cumulative dose of corticosteroid were seen in the patients who did not achieve PR at week 12 than in those who did, regardless of their CR status, at year 3.ConclusionsLack of PR at week 12 predicts a lower likelihood of achieving CR at 3 years and a higher SDI.