renal response
Recently Published Documents


TOTAL DOCUMENTS

670
(FIVE YEARS 68)

H-INDEX

44
(FIVE YEARS 5)

Author(s):  
Scott A. Hubers ◽  
Siu‐Hin Wan ◽  
Fadi W. Adel ◽  
Sherry L. Benike ◽  
John C. Burnett ◽  
...  

Background Phosphodiesterase V (PDEV) is upregulated in heart failure, leading to increased degradation of cGMP and impaired natriuresis. PDEV inhibition improves the renal response to B‐type natriuretic peptide in animal models. We tested the hypothesis that long‐term PDEV inhibition would improve renal function and cardiorenal response after short‐term volume load in subjects with pre–heart failure. Methods and Results A total of 20 subjects with pre–heart failure (defined as an ejection fraction ≤45% without previous diagnosis of heart failure) and renal impairment were randomized in a 2:1 manner to tadalafil or placebo. Baseline echocardiography and renal clearance study were performed, followed by a short‐term saline load and repeated echocardiography and renal clearance study. Subjects then received either tadalafil at a goal dose of 20 mg daily or placebo, and the study day was repeated after 12 weeks. Long‐term tadalafil did not improve glomerular filtration rate (median increase of 2.0 mL/min in the tadalafil group versus 13.5 mL/min in the placebo group; P =0.54). There was no difference in urinary sodium or cGMP excretion with PDEV inhibition following short‐term saline loading. Conclusions Glomerular filtration rate and urinary sodium/cGMP excretion were not significantly different after 12 weeks of tadalafil compared with placebo. These results do not support the use of PDEV inhibition to improve renal response in patients with pre–heart failure. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01970176.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1670-1670
Author(s):  
Yifei Zhang ◽  
Amandeep Godara ◽  
Stacey Pan ◽  
Denis Toskic ◽  
Teresa Fogaren ◽  
...  

Abstract Introduction: Daratumumab in combination with cyclophosphamide, bortezomib and dexamethasone (Dara/CyBorD) is the only FDA approved therapy for newly diagnosed systemic light-chain (AL) amyloidosis (N Engl J Med 2021;385:46). Belantamab mafodotin is a novel anti-BCMA immunoconjugate with humanized IgG1 anti-BCMA monoclonal antibody conjugated to a microtubule-disrupting agent, monomehtyl auristatin F (MMAF) via a non-cleavable linker (Blood 2014;123:3128). Phase I/II studies in heavily pre-treated multiple myeloma patients showed single agent clinical activity with overall response rates ranging from 30-60%, with majority of responses being durable at 13 months of follow-up. Toxicity profile included keratopathy, thrombocytopenia and anemia (Blood Cancer J 2019;9:37; Lancet Oncol 2020;21:207). Based on these results, belantamab mafadotin (BLM; Blenrep) was FDA approved for relapsed myeloma. A role for new agents such as BLM in AL has not been previously reported. Here we report outcomes of six patients who received BLM at different centers for relapsed refractory (RR) AL associated with myeloma. Methods: In this retrospective study we identified AL patients with RR disease who received at least one dose of BLM. In a multi-institutional collaboration we collected demographic, medical history, laboratory, pathologic and treatment/response data on patients with myeloma and biopsy-proven AL who had received BLM. Laboratory assessment including evaluations for hematologic and organ response was done as per standard criteria and toxicity assessed as per CTCAE v6.0. Results: We identified 6 patients, 3M/3F, from 4 centers; baseline characteristics and treatment data are provided in Table 1. Baseline median age was 61 years (range, 51-74) and median marrow plasmacytosis and iFLC were 40% (10-90) and 868mg/L (145-5324). Four patients had AL λ-type and 2 κ-type, and 5 of 6 had cardiac involvement while 3 had additional organ involvement (renal, GI, nervous system). Prior to initiating BLM the median number of lines of prior therapy was 6 (range, 5-10), including daratumumab, bortezomib and lenalidomide, and prior to initiating BLM marrow assessment showed a median plasmacytosis of 23%. BLM at 2.5 mg/kg was given as an intravenous infusion over the course of 30 minutes every three weeks after ophthalmologic exam clearance until discontinuation for progression or toxicity. At a median follow-up of 4.5 months, 5 patients (83%) achieved hematological responses (HR) with 3 (50%) achieving complete hematological responses (CR) by standard criteria (J Clin Oncol 2012;30:4541). Time to HR ranged from 3 to 150 days. Cardiac response was seen in all but 1 patient, with time to response ranging from 11 to 96 days. One patient had a renal response; response assessment is not yet available for 2 other patients with renal involvement. The most common toxicity was keratopathy (grade 1-2). BLM was held after the first dose in one patient who had been heavily pre-treated and had extensive cardiac and pulmonary AL and multiple sites of FDG-avid progressive myeloma bone disease. Two days after administration of the first dose of BLM, this 51-year-old man was admitted to hospital for dyspnea, developed atrial fibrillation and ventricular tachycardia, and briefly required cardiac resuscitation without intubation with return of spontaneous circulation after 6 minutes. This patient achieved a CR after one dose of BLM that has been stable for over 5 months with marked clinical improvement. A 62 year-old woman with cardiac and renal AL has achieved a CR durable for over 16 months with cardiac and renal responses. Conclusions: In this group of 6 patients with RR AL with myeloma, HR and cardiac response rates were impressive at 83% and 80%, respectively. One patient who had 24-hour urine protein evaluation also achieved a renal response. Time to response was rapid with 2 patients achieving HR within a week of starting treatment, and the rest within five months. Additionally, 3 of 6 patients achieved CR, 1 had no clonal plasma cells in the marrow and another clonal disease detectable only by MRD. In this retrospective multi-institutional cohort BLM resulted in rapid reduction of iFLC and induced critical organ responses. These data provide preliminary evidence for the clinical activity of BLM in RR AL. Results of the on-going phase 2 clinical trial in the European Myeloma Network (EMN27; NCT04617925) are awaited with great interest. Figure 1 Figure 1. Disclosures Sborov: Sanofi: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy; SkylineDx: Consultancy. Comenzo: Karyopharm: Research Funding; Prothena Biosciences: Consultancy, Research Funding; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Unum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Caelum: Consultancy, Research Funding; Janssen: Patents & Royalties: WO2016187546A1, Research Funding. Kansagra: Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Cota Health: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Alynylam: Membership on an entity's Board of Directors or advisory committees.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1660-1660
Author(s):  
Jian Hou

Abstract Background: RI is one of the most common complications of multiple myeloma (MM). The incidence of RI at diagnosis ranges from 20% to 50%, Bortezomib-based regimens remain the cornerstone of the management of myeloma-related RI, and the addition of a third drug to Vd seems to be beneficial,but not for sure. Pomalidomide is extensively metabolized by liver, with only approximately 2% of active substance eliminated in the urine, which suggests that RI may not affect pomalidomide exposure in a clinically relevant manner. The MM013(phase 2, NCT02045017) trial confirmed that Pomalidomide could be safely used in RRMM with RI and achieved good response in MM and Renal function. The OPTIMISMM (phase 3, NCT01734928) trial Subgroup analysis reported efficacy and safety of PVd vs Vd at first relapse by renal function (creatinine clearance [CrCl] < 60 vs ≥ 60 mL/min) before. The ORR significantly improved with PVd vs Vd regardless of renal status (P < .001 for both renal groups): 91.4% vs 53.6% (≥ VGPR,54.3% vs 21.4%) in the CrCl < 60 mL/min group and 89.5% vs 55.2% (≥ VGPR, 64.5% vs 23.0%) in the CrCl ≥ 60 mL/min group. Since RVd is the standard treatment for NDMM patients, We believe that standard dose Pomalidomide plus Vd will be very promising for NDMM patients with RI Study Design/ Methods: This is a multicenter, prospective, randomized phase 2 study designed to evaluate the efficacy and safety of PVd Versus Vd in Patients With NDMM and Renal Impairment(RI). Eligible patients were aged ≥18 years and had a diagnosis of multiple myeloma, measurable disease, and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were required to have had no prior antimyeloma regimen. The definition of RI is based on reduced creatinine clearance (15 mL/min≤CrCl<60 mL/min) without indication for hemodialysis, which have to be the result of myeloma. Key exclusion criteria included previous course of chemotherapy; uncontrolled malignant disorder, infection, or peripheral neuropathy, patients on dialysis will be excluded too. Approximately 79 patients will be randomized 2:1(Figure 1) to Arm A (PVd) or Arm B (Vd), both Arms will have induction therapy for 4 cycles. In Arm A, patients will receive pomalidomide 4 mg on days 1-14 of each cycle. Bortezomib 1.3 mg/m 2 on days 1, 4, 8, and 11 of each cycle. Dexamethasone 20mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of each cycle (21-day cycles); In Arm B, patients will receive the same bortezomib and dexamethasone as Arm A. The primary endpoint is ≥VGPR, the secondary endpoints are MRD(-) rate,renal response,Immune function,Renal tubular function, and safety. Myeloma response and renal response will be assessed by the International Myeloma Working Group criteria after each cycle. Eficacy analyses will be performed on the intent-to-treat population; Safety analysis will be conducted in the safety population, which are composed of all patients who received ≥1 dose of study medication. The trial is currently enrolling and will be open in 8 sites in China. Disclosure:Research Sponsor : CHIATAI TIANQING PHARMACEUTICAL GROUP. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Pomalidomide which was approved in RRMM will be used in NDMM with RI


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2715-2715
Author(s):  
Diana Zhang ◽  
Danai Dima ◽  
Mumtu Lalla ◽  
Denis Toskic ◽  
Ping Zhou ◽  
...  

Abstract Introduction: In systemic light-chain amyloidosis (AL) aberrant clonal free immunoglobulin light chains (FLC) misfold and deposit in vital organs causing severe dysfunction (Nat Rev Dis Primers 2018;4:38). With anti-plasma cell therapy that reduces or eliminates the involved FLC (iFLC), defined organ responses can occur (N Engl J Med 2021;385:46, Blood Rev 2019;37:100581, Leukemia 2017;31:136, Blood 2014;124:2325). We asked whether the timing of individual organ responses may be influenced by the number of organs involved at diagnosis; therefore we evaluated the pattern of responses in patients with the two most commonly involved organs (heart, kidney) who achieved deep hematologic responses to therapy (CR=complete response, VGPR=very good partial response)(J Clin Oncol 2012;30:4541). We examined whether the rate of and time to organ response varied in patients with only heart or kidney or heart and kidney involvement, and whether the depth of hematologic response impacted the pattern of organ response. Methods: We performed a retrospective analysis AL patients diagnosed by tissue biopsy between 2007-2019 who had heart and/or kidney involvement at diagnosis and achieved hematologic CR/VGPR with treatment. Mann-Whitney was used to compare rates of organ responses and log-rank tests were applied to compare times to organ response among the subgroups as well as overall survival (OS) differences based on iFLC responses and on organ responses. Results were considered to be significant if two-sided P-value was less than or equal to 0.05. Results: We identified 111 patients with a median age of 62.5 years (range, 40-80) who met these criteria, 65 of whom (59%) were male. Cardiac involvement only was present in 34 (30.6%), renal involvement only in 31 (28.0%), and both cardiac and renal involvement in 46 (41.4%). Table 1 highlights patient characteristics. The median OS for the entire cohort was 112 months (95% CI 100-NA). The overall cardiac response rate was 62.5%, with a median time to response of 8 months (range, 1-73 months). Overall renal response rate was 67.1% with a median time to response of 10 months (range, 1-57 months). Log-rank analysis showed a significant difference in the OS based on post treatment iFLC levels (<10 vs. 10-20 vs. >20 mg/L) as we have previously described (Am J Hematol 2021;96:E20). Patients with kidney involvement only had significantly improved overall survival (OS) compared to those with cardiac involvement only (p=0.05), as expected. However, there was no difference in the OS of patients with cardiac only vs. cardiac and renal involvement (p=0.58), while there was a trend towards shorter OS in patients with cardiac and renal vs renal (p=0.09). The lower iFLC levels achieved post-treatment influenced cardiac response rate (p=0.07), and significantly impacted renal response rate (p<0.01). For patients with cardiac involvement, iFLC responses did not have a significant impact on time to cardiac response, whereas for patients with renal involvement, faster responses were noted in those achieving lower iFLC levels (p=0.017) (Figure 1). There was no significant difference in time to cardiac response between patients with cardiac only vs. cardiac and renal involvement (p=0.93) whereas patients with renal only vs cardiac and renal involvement had a faster time to renal response (medians 14 (range, 10-29) vs 43 (13-not reached) months, p=0.018) (Figure 2). Conclusion: In AL patients with renal involvement who achieve CR/VGPR with treatment, post-treatment iFLC levels and co-presence of cardiac involvement play significant roles in the timing of renal responses. In AL patients with cardiac involvement who achieve CR/VGPR, post-treatment iFLC levels but not the co-presence of renal involvement influences the rate of cardiac response but neither influences the timing. These differences may be due to organ-specific factors such as proteomic adaptations or relative iFLC toxicity or complex cardio-renal hormonal interactions. Further hypothesis-driven study of these differences is warranted in this era of new and effective anti-plasma cell therapies. Figure 1 Figure 1. Disclosures Comenzo: Prothena Biosciences: Consultancy, Research Funding; Karyopharm: Research Funding; Takeda: Research Funding; Unum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Caelum: Consultancy, Research Funding; Janssen: Patents & Royalties: WO2016187546A1, Research Funding.


2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A252-A252
Author(s):  
Ala Abudayyeh ◽  
Liye Suo ◽  
Heather Lin ◽  
Omar Mamlouk ◽  
Cassian Yee ◽  
...  

BackgroundInflammatory response in unintended tissues and organs associated with the use of immune checkpoint inhibitors also known as immune related adverse events (irAEs) is a management challenge, and renal irAEs are associated with increased patient morbidity and mortality. The most common renal toxicity is acute interstitial nephritis (AIN), characterized by infiltration of renal tissue with immune cells, and may be analogous to kidney transplant rejection. Using both clinical variables and tissue findings we evaluated a large cohort of ICI cases to determine predictors of renal response and overall survival.MethodsWe retrospectively reviewed all patients treated with ICI (August 2007 to August 2020) at MD Anderson Cancer Center. A total of 38 patients with biopsy confirmed AIN and available tissue were identified. All slides were reviewed by two board certified renal pathologists and the severity of inflammation and chronicity was graded using transplant rejection BANFF criteria. Patients were categorized as renal responders if creatinine improved or returned to baseline after treatment and non-responders if it did not. Fisher’s exact tests for categorical variables and t-test/ANOVA or the counterparts of the non-parametric approaches (Wilcoxon rank-sum or Kruskal-Wallis) for continuous variables were used to compare patient‘s characteristics between groups. The distribution of overall survival (OS) was estimated by the Kaplan-Meier method. Log-rank test was performed to test the difference in survival between groups.ResultsBased on the detailed pathological findings, patients with increased interstitial fibrosis were less likely to have renal response with treatment compared to patients with less fibrosis, (p < 0.05). Inflammation, tubulitis, number of eosinophils and neutrophils had no impact on renal response. Patients with response within 3 months of AKI treatment had a superior OS in comparison to patients who responded late (12-month OS rate: 77% vs 27%, p < 0.05). Notably, patients who received concurrent ICI and achieved renal response within 3 months had the best OS while those who did not receive concurrent ICI nor achieved renal response had worst OS (12-month OS rate: 100% (renal response and concurrent ICI) vs 72% ( renal response with no concurrent ICI), vs 27% ( no renal response and nonconcurrent ICI) (p < 0.05).ConclusionsThis is the first analysis of ICI induced nephritis where a detailed pathological and clinical evaluation was performed to predict renal response. Our findings highlight the importance of early diagnosis and treatment of ICI-AIN while continuing concurrent ICI therapy.Ethics ApprovalThis retrospective study was approved by the institutional review board at The University of Texas MD Anderson Cancer Center, and the procedures followed were in accordance with the principles of the Declaration of Helsinki.


2021 ◽  
Vol 124 ◽  
pp. 102729
Author(s):  
Mariele Gatto ◽  
Francesca Saccon ◽  
Laura Andreoli ◽  
Elena Bartoloni ◽  
Francesco Benvenuti ◽  
...  

2021 ◽  
Vol 81 (1) ◽  
pp. 100-107
Author(s):  
Richard A Furie ◽  
Gustavo Aroca ◽  
Matthew D Cascino ◽  
Jay P Garg ◽  
Brad H Rovin ◽  
...  

ObjectiveRandomised trials of type I anti-CD20 antibodies rituximab and ocrelizumab failed to show benefit in proliferative lupus nephritis (LN). We compared obinutuzumab, a humanised type II anti-CD20 monoclonal antibody that induces potent B-cell depletion, with placebo for the treatment of LN in combination with standard therapies.MethodsPatients with LN receiving mycophenolate and corticosteroids were randomised to obinutuzumab 1000 mg or placebo on day 1 and weeks 2, 24 and 26, and followed through week 104. The primary endpoint was complete renal response (CRR) at week 52. Exploratory analyses through week 104 were conducted. The prespecified alpha level was 0.2.ResultsA total of 125 patients were randomised and received blinded infusions. Achievement of CRR was greater with obinutuzumab at week 52 (primary endpoint, 22 (35%) vs 14 (23%) with placebo; percentage difference, 12% (95% CI −3.4% to 28%), p=0.115) and at week 104 (26 (41%) vs 14 (23%); percentage difference, 19% (95% CI 2.7% to 35%), p=0.026). Improvements in other renal response measures, serologies, estimated glomerular filtration rate and proteinuria were greater with obinutuzumab. Obinutuzumab was not associated with increases in serious adverse events, serious infections or deaths. Non-serious infusion-related reactions occurred more frequently with obinutuzumab.ConclusionsImproved renal responses through week 104 were observed in patients with LN who received obinutuzumab plus standard therapies compared with standard therapies alone. Obinutuzumab was well tolerated and no new safety signals were identified.Trial registration numberNCT02550652.


QJM ◽  
2021 ◽  
Vol 114 (Supplement_1) ◽  
Author(s):  
Ashraf Mahmoud Okba ◽  
Nehal Elfawy Mahmoud ◽  
Mariam Maged Amin ◽  
Mariam Ahmed Mohamed Mamdouh

Abstract Background Tubulointerstitial inflammation (TI) associated with systemic lupus erythematosis is an increasing finding in lupus nephritis. TI severity may have prognostic significance in the renal outcomes of lupus nephritis. Here, we aimed to determine whether non-albumin proteinuria is associated with TI severity and with the renal response in lupus nephritis. Objective To investigate the possible association between non-albumin proteinuria, tubulointerstial inflammation severity and poor renal response after immunosuppressive treatment. Patients and Methods This is a case series study which was conducted on 100 patients with systemic lupus erythematosis recruited from the outpatient clinic of Clinical Immunology at Ain Shams University Hospitals. Subject ages were between 13-53 years old, each one was subjected to detailed history, physical examination, laboratory investigations including serum creatinine before and after treatment, protein/creatinine ratio before and after treatment, albumin/creatinine ratio, ESR, CRP, CBC, C3 C4, anti DNA, eGFR and renal biopsy Results Our results showed that non-albumin proteinuria (uPCR − uACR) was significantly higher in patients with moderate-to-severe TI than in patients with no-tomild TI. Further, higher uPCR − uACR levels at baseline were associated with poor renal response after 6 months of treatment. Conclusion we found that non-albumin proteinuria (uPCR-uACR) is associated with severe tubulointerstitial inflammation (TI) in lupus nephritis.


2021 ◽  
Vol 21 ◽  
pp. S23-S24
Author(s):  
Eli Muchtar ◽  
Brendan Wisniowski ◽  
Giovanni Palladini ◽  
Paolo Milani ◽  
Giampaolo Merlini ◽  
...  

Sign in / Sign up

Export Citation Format

Share Document