Extended infusion of rituximab combined with steroids is effective in inducing remission and reducing relapse in adult minimal change disease

Abstract Background Minimal change disease is a common cause of nephrotic syndrome in adults. Higher relapse rate put patients at risk of steroids toxicity due to long-term exposure. Rituximab has been suggested to maintain long time remission and withdraw steroids and other immunosuppressants with fewer adverse events. However, optimal dose and dosing interval have not been explored. Methods Twenty-five patients were enrolled from 2017-10 to 2020-03 in Nanfang Hospital in China. Clinical and biological data were extracted from medical records and laboratory databases. Therapy composed of 375mg/m2 rituximab once three weeks for 3 dose and corticosteroid was applied. Complete remission was defined as reduction of proteinuria to 0.3g/d. Remission rate, relapse rate, steroids used before and after rituximab therapy and adverse effects were documented at a mean time of 14.71 months. Results Twenty-two patients achieved complete remission for an average of 3.26 months and only 3 patients experienced one relapse respectively during the follow-up period. The mean remission maintenance time was 11.6 months, and was 5 months after steroids withdrawal. Steroids dose at last follow-up was 6.09mg/d, which was significantly reduced compared to 28.15mg/d before rituximab. Relapse rate before and after rituximab was 1.43 and 0.1, respectively. Only four minor adverse events were recorded. Conclusions Therapy consisted of 375mg/m2 rituximab once three weeks for 3 dose combined with corticosteroid is effective in inducing remission in adult patients with minimal change disease. Both of the relapse rate and dose of steroids used are significantly decreased with fewer side effects.

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Efficacy and safety of rituximab in adult frequent-relapsing or steroid-dependent minimal change disease or focal segmental glomerulosclerosis: a systematic review and meta-analysis

Clinical Kidney Journal ◽

10.1093/ckj/sfaa191 ◽

2020 ◽

Author(s):

Cheng Xue ◽

Bo Yang ◽

Jing Xu ◽

Chenchen Zhou ◽

Liming Zhang ◽

...

Keyword(s):

Systematic Review ◽

Adverse Events ◽

Focal Segmental Glomerulosclerosis ◽

Minimal Change Disease ◽

Meta Analysis ◽

Minimal Change ◽

Efficacy And Safety ◽

Segmental Glomerulosclerosis ◽

Steroid Dependent

Abstract Background The efficacy and safety of rituximab (RTX) in adult frequent-relapsing (FR) or steroid-dependent (SD) nephrotic syndrome (NS), including minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS), are still inconclusive. Methods We performed a systematic review and meta-analysis registered in PROSPERO (CRD42019148102) by pooling data of cohort studies or case series on adult patients with difficult-to-treat NS. Steroid-resistant NS was excluded. The primary outcomes were the complete remission (CR) rate and the relapse rate. Partial remission (PR) rate, no response (NR) rate and adverse events were the secondary outcomes. A random-effects model was performed for all the outcomes. Results We included 21 studies involving 382 adult MCD/FSGS subjects with a median follow-up duration from 12 to 43 months. RTX treatment induced a pooled 84.2% CR rate [95% confidence interval (CI): 67.7–96.3%], while MCD patients had a high 91.6% CR rate and FSGS patients a moderate 43% CR rate. However, 27.4% (95% CI 20.7–34.5%) of the patients relapsed during the follow-up. The pooled PR and NR rates were 5.8% (95% CI 1.2–12.5%) and 5.2% (95% CI 0.0–15.0%), respectively. RTX was associated with trivial adverse events and good tolerance. Conclusions In summary, by pooling results of current pilot studies, RTX may be an effective and relatively safe alternative for most adult FR or SD MCD/FSGS to displace calcineurin inhibitors or prednisone in the hierarchy of treatment. More clinical trials comparing RTX with other immunosuppressants and concerning the long-term adverse events are needed.

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Association of initial prednisolone dose with remission, relapse, and infectious complications in adult-onset minimal change disease

Clinical and Experimental Nephrology ◽

10.1007/s10157-021-02119-3 ◽

2021 ◽

Author(s):

Kaori Tanabe ◽

Ken-ichi Samejima ◽

Fumihiro Fukata ◽

Takaaki Kosugi ◽

Hideo Tsushima ◽

...

Keyword(s):

Initial Treatment ◽

Minimal Change Disease ◽

Cox Regression ◽

Remission Rate ◽

Infectious Complications ◽

Minimal Change ◽

Multicenter Cohort Study ◽

Prednisolone Dose ◽

Significant Difference

Abstract Background A dose of 0.5–1 mg/kg/day of prednisolone (PSL) is administered for the initial treatment of minimal change disease (MCD). However, little is known about the optimal PSL dose for the initial treatment of MCD. Methods We conducted a retrospective multicenter cohort study of treatment-naive adult patients with MCD diagnosed by renal biopsy from 1981 to 2015 in whom PSL monotherapy was performed as the initial treatment. The exposure of interest was an initial median PSL dose of < 0.63 mg/kg/day (Group L) compared to ≥ 0.63 mg/kg/day (Group H). Cumulative remission and relapse after remission were compared between these groups using Cox regression adjusted for baseline characteristics. Results Ninety-one patients met the inclusion criteria. During a median follow-up of 2.98 years, 87 (95.6%) patients achieved complete remission, and 47.1% relapsed after remission. There was no significant difference in the remission rate between the groups at 4 weeks of follow-up (66.7 vs. 82.6%). The median time to remission in Group L was comparable to that in Group H (17.0 vs. 14.0 days). A multivariable Cox hazard model revealed that the initial PSL dose was not a significant predictor of remission. The cumulative steroid doses at 6 months, 1 year, and 2 years after treatment initiation were significantly lower in Group L than in Group H. Conclusion The initial PSL dose was not associated with time to remission, remission rate, time to relapse, or relapse rate. Therefore, a low initial steroid dose may be sufficient to achieve remission.

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RNAi inhibition of angiopoietin-like protein 3 (ANGPTL3) with ARO-ANG3 mimics the lipid and lipoprotein profile of familial combined hypolipidemia

European Heart Journal ◽

10.1093/ehjci/ehaa946.3331 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

G.F Watts ◽

C Schwabe ◽

R Scott ◽

P Gladding ◽

D Sullivan ◽

...

Keyword(s):

Adverse Events ◽

Dose Response ◽

Minimal Change ◽

Funding Source ◽

Private Company ◽

Good Tolerability ◽

Duration Of Action ◽

Mixed Dyslipidemia ◽

Genetic Deficiency

Abstract Background Elevated LDL-C and triglyceride rich lipoproteins (TRLs) are independent risk factors for cardiovascular disease (CVD). Genetic deficiency of angiopoietin-like protein 3 (ANGPTL3) is associated with reduced circulating levels of LDL-C, triglycerides (TGs), VLDL-C, HDL-C and reduced CVD risk, with no described adverse phenotype. ARO-ANG3 is a RNA interference drug designed to silence expression of ANGPTL3. Single doses of ARO-ANG3 have been shown to reduce ANGPTL3, TGs, VLDL-C and LDL-C in healthy volunteers (HVs, AHA 2019). We report the effects of multiple doses of ARO-ANG3 in HVs with a focus on the duration of action. Methods ARO-ANG3 was administered subcutaneously to HVs on days 1 and 29 at doses of 100, 200 or 300 mg (n=4 per group). Measured parameters included ANGPTL3, LDL-C, TGs, VLDL-C and HDL-C. Follow up is ongoing. Results All HVs have received both doses and follow-up is currently through week 16 (12 weeks after second dose). Mean nadir for ANGPTL3 levels occurred 2 weeks after the second dose (−83–93%) with minimal change for 200 and 300 mg but 16% recovery for 100 mg at week 16. Mean TGs and VLDL-C reached nadir earlier (3 wks, −61–65%) without apparent dose response and minimal change for any dose at wk 16. LDL-C nadir occurred 4–6 wks after the second dose (−45–54%), again with minimal evidence for dose response or change through wk 16. HDL-C was reduced 14–37% at wk 16. ARO-ANG3 was well tolerated without serious or severe adverse events or dropouts related to drug. The most common adverse events have been headache and upper respiratory infections. Conclusions Genetic deficiency of ANGPTL3 is a cause of familial combined hypolipemia and is associated with a decreased risk of CVD. Using RNAi to selectively suppress ANGPTL3 production reproduces these genetic effects with a duration of at least 12 weeks following a second dose and with good tolerability over 16 wks. ANGPTL3 inhibition results in lowering of LDL-C and TRLs which may confer protection against CVD in patients with atherogenic mixed dyslipidemia. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Arrowhead Pharmaceuticals

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Predictors of adverse prognosis in patients with infective endocarditis in a surgical referral center

European Heart Journal ◽

10.1093/ehjci/ehaa946.1880 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

V Scheggi ◽

I Olivotto ◽

N Ceschia ◽

I Merilli ◽

V Andrei ◽

...

Keyword(s):

Renal Failure ◽

Infective Endocarditis ◽

Adverse Events ◽

Ejection Fraction ◽

Relapse Rate ◽

Left Ventricular Ejection ◽

All Cause Mortality ◽

Fatal Adverse Events

Abstract Background Despite optimal medical and surgical treatment, mortality in infective endocarditis (IE) remains high. Aim of this study was to identify predictors of long term mortality for any cause, adverse event rate, relapse rate and valvular dysfunction at follow-up, in a high-volume surgical center. Methods We retrospectively analyzed 358 consecutive patients (127 women) admitted to our department with definite diagnosis of IE not device-related. IE occurred on native valves in 224 patients (63%); the infection involved the aortic valve in 192 (54%), mitral valve in 139 (39%) and tricuspid valve in 26 (7%). Overall 285 (80%) patients underwent surgery and 73 (20%) were treated conservatively, 38 due to absence of surgical indication and 35 due to refusal or prohibitive surgical risk. Long-term follow-up was obtained by structured telephone interviews. Primary endpoints were all-cause mortality, freedom from recurrent endocarditis, postoperative incidence of major adverse events (hospitalization for any cause, pace-maker implantation, new onset of atrial fibrillation, sternal dehiscence), worsening of left ventricular ejection fraction (LVEF) and valvular dysfunction. Results Mean age was 65 years (SD 15.2). Mean vegetation length was 8.9 mm (SD 7.6). Endocarditis was left-sided in 332 (93%). Average follow-up was 6 months. At univariable analysis, mortality was associated with female gender (p=0.031), age (p<0.001), higher EuroSCORE 2 (p<0.001), chronic renal failure (p<0.001), diabetes (p=0.002), brain embolism on presentation (p=0.05), double valve infection (p=0.008), low ejection fraction (p<0.001), paravalvular extension (p=0.031), prosthetic infection (p=0.018), exclusion from surgery if indicated (p<0.001), high procalcitonin levels (p=0.035); factors associated with a significantly lower mortality were streptococcal infection (p=0.04; OR 0.34) and early surgery (p=0.009, OR 0.55). At multivariable analysis independent predictors of all-cause mortality were lower EF, EuroSCORE2, procalcitonin levels and diabetes. Non-fatal adverse events were associated with renal failure (p 0.035, OR 2.8). Relapse rate was associated with S aureus infection (p=0.005, OR 3.8), right-sided endocarditis (p<0.001, OR 6.7) and drug abuse (p<0.001, OR 9.4). Conclusions The present study shows that low EF, EuroSCORE2, procalcitonin levels and diabetes are independent predictors of death in patients with IE. Non-fatal adverse events are more frequent in patients with renal failure. Relapse rate is higher in drug abusers. These informations may help personalize follow-up strategies after acute admission for IE. Funding Acknowledgement Type of funding source: None

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Glucocorticoids and steroid sparing medications monotherapies or in combination for IgG4-RD: a systematic review and network meta-analysis

Rheumatology ◽

10.1093/rheumatology/kez380 ◽

2019 ◽

Vol 59 (4) ◽

pp. 718-726 ◽

Cited By ~ 6

Author(s):

Dina Omar ◽

Yu Chen ◽

Ye Cong ◽

Lingli Dong

Keyword(s):

Adverse Events ◽

Maintenance Therapy ◽

Relapse Rate ◽

Induction Therapy ◽

Remission Rate ◽

Meta Analysis ◽

Immunosuppressive Agents ◽

Current Evidence ◽

Treatment Groups ◽

Events Data

Abstract Objective To assess the safety and efficacy of glucocorticoids (GCs), immunosuppressive agents (IM) and rituximab (RTX), alone or in combination, for the treatment of IgG4-RD. Methods Relevant articles published were searched in the databases with relevant key words. Network meta-analysis was conducted, with various outcomes including relapse rate, remission rate and adverse events. Data were calculated with odds ratio (ORs) and 95% CI. P-score was used to rank the treatments. Results A total of 15 studies involving 1169 patients were included. Network meta-analysis indicated that RTX maintenance therapy had the lowest relapse rate of all treatments (OR = 0.10, 95% CI [0.01, 1.63]), whereas GCs + IM was associated with a lower relapse rate compared with GCs alone (OR = 0.39, 95% CI [0.20, 0.80]). Further, patients treated with GCs + IM had a higher remission rate than those given GCs (OR= 3.36, 95% CI [1.44, 7.83]), IM (OR= 55.31, 95% CI [13.73, 222.73]) monotherapies or RTX induction therapy only (OR= 7.38, 95% CI [1.56, 34.94]). The rate of adverse events was comparable among the different treatment groups. Conclusion Treatment of IgG4-RD patients with GCs and IM was associated with higher remission rates and lower relapse rates, as well as comparable safety profiles compared with GC, IM and RTX induction therapy. RTX maintenance therapy had a larger reduction in the relapse rate compared with GC and IM. The current evidence should be carefully scrutinized as the included studies were observational in design. Larger randomized controlled trials are needed to confirm.

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Busulfan/etoposide--initial experience with a new preparatory regimen for autologous bone marrow transplantation in patients with acute nonlymphoblastic leukemia

Blood ◽

10.1182/blood.v81.2.319.319 ◽

1993 ◽

Vol 81 (2) ◽

pp. 319-323 ◽

Cited By ~ 47

Author(s):

NJ Chao ◽

AS Stein ◽

GD Long ◽

RS Negrin ◽

MD Amylon ◽

...

Keyword(s):

Bone Marrow ◽

Complete Remission ◽

Median Time ◽

Relapse Rate ◽

Disease Free Survival ◽

Autologous Bone Marrow ◽

Free Survival ◽

Acute Nonlymphoblastic Leukemia ◽

Disease Free

Abstract Current intensive chemotherapy for acute nonlymphoblastic leukemia (ANLL) results in a complete remission in the majority of patients. Unfortunately, the duration of remission is short and most of the patients will experience a relapse of their underlying disease. Autologous bone marrow (BM) transplantation is being explored as a treatment modality designed to improve relapse-free survival. We have conducted a phase II trial exploring the combination of busulfan (16 mg/kg) and etoposide (60 mg/kg) in an attempt to improve antitumor efficacy using this novel preparative regimen. To date, 50 patients (48 with ANLL and 2 patients with biphenotypic acute leukemia) have been treated. The first 20 patients received unmanipulated BM; 28 patients subsequently received 4-hydroperoxycyclophosphamide (4–HC) (60 micrograms/mL)-purged bone marrow, and 2 patients with biphenotypic acute leukemia received both 4–HC (60 micrograms/mL) and etoposide (5 micrograms/mL)-purged BM. Thirty-four patients were in first complete remission (CR1), 12 patients in second complete remission (CR2), and 4 patients in relapse. The median time from first complete remission to BM harvest was 3 months (range, 0.8 to 4) compared with median time of 2 months (range, 1.5 to 5.0) for patients in second complete remission. The median time from harvest to transplant was 1 month for both groups (range, 0.4 to 36). A median of 0.7 x 10(8) (range, 0.2 to 1.4) mononuclear cells were infused. Patients achieved an absolute neutrophil count of > or = 500/microL at a median of 26 days (range, 13 to 96), an untransfused platelet count > or = 20,000/microL at a median of 56 days (range, 15 to 278) and a sustained hematocrit > or = 30% at a median of 50 days (range, 19 to 116). Twenty-six patients are alive and in continued CR. Follow-up of the surviving patients ranged from 6 months to 66 months with a median follow-up of 31 months. Patients receiving purged BM have an actuarial disease-free survival of 57% with a relapse rate of 28% compared with patients receiving unpurged BM whose actuarial disease-free survival is 32% with a relapse rate of 62% (P = .06 for relapse rate). The most significant extramedullary toxicities for this regimen are hepatic and cutaneous (including mucositis). The BU/VP-16 regimen is associated with a significant proportion of patients surviving disease free, especially in the group receiving purged BM. Whether this regimen offers a substantial improvement in disease-free survival over currently used regimens will require a prospective randomized study.

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Immunochemotherapy with Rituximab Improves Molecular CR Rate and Outcome In CD20+ B-Lineage Standard and High Risk Patients; Results of 263 CD20+ Patients Studied Prospectively In GMALL Study 07/2003

Blood ◽

10.1182/blood.v116.21.170.170 ◽

2010 ◽

Vol 116 (21) ◽

pp. 170-170 ◽

Cited By ~ 38

Author(s):

Dieter Hoelzer ◽

Andreas Huettmann ◽

Felix Kaul ◽

Sebastian Irmer ◽

Nadja Jaekel ◽

...

Keyword(s):

Overall Survival ◽

High Risk ◽

Complete Remission ◽

Relapse Rate ◽

Remission Rate ◽

Supportive Therapy ◽

High Risk Patients ◽

Tumour Load ◽

Risk Patients ◽

Standard Risk

Abstract Abstract 170 The effect of Rituximab in conjunction with a chemo induction and consolidation therapy was studied in CD20+, Ph/BCR-ABL negative B-precursor ALL (Pre-B/Common) in the GMALL Study 07/2003. The rationale were encouraging results with combined intensive chemotherapy and Rituximab in CD20+ adult Burkitt lymphoma / leukemia. Furthermore that in previous GMALL studies, improvement of B-precursor ALL by intensification of chemotherapy was limited and the observation that patients with CD20+ cells (antigen expression >20%) had an inferior outcome in adult ALL (Thomas et al. Blood 2009. 113;6330). Aim: In standard risk (SR) patients the aim was to increase the rate of molecular remission (Mol. CR) thereby decreasing the relapse rate and in high risk (HR) patients to reduce the pre-transplant tumour-load and thereby reducing the relapse rate after SCT which was 30–40% in previous GMALL studies. Materials and Methods: Adult ALL patients (15 – 55 years) with standard risk B-precursor ALL being CD20 pos. received Rituximab 375 mg/m2 at day -1 before each induction course (phase I and II), the re-induction course and before each of the six consolidations for a total of 8 doses. High Risk patients, defined as WBC > 30.000 and/or late CR > 4 weeks, which are candidates for a stem cell transplantation in CR 1 after wk 16, received Rituximab three times (d -1 ind. I/II and Cons. I) before SCT. Patients receiving Rituximab were compared with earlier CD20+ patients in the GMALL study 07/2003 with identical chemo- and supportive therapy but no Rituximab. MRD method and chemo backbone was described earlier [Brüggemann, Blood 2006: 107;1116]. Results: A total of 263 CD20 pos. patients were analyzed in the GMALL study 07/2003; 196 were SR and 67 HR patients. 181 received Rituximab (R+ arm) and were compared to a cohort of 82 patients earlier recruited without Rituximab (R- arm). In the SR there was no difference in the results of induction therapy with a CR rate of 94 % and 91 % in the R+ vs. R- patients. There was also no difference in ED rate 5% vs. 3% or failure/PR 1% vs. 5%. However, MRD course differed substantially. Decrease in MRD load in the R+ vs. R- arm was faster with a Mol CR (MRD <10-4) rate of 57% vs. 27% at day 24 and of 90% vs. 59% at wk 16. Probability for continuous complete remission (CCR) at 5 years was 80% vs. 47% for R+ vs. R- pts. and for overall survival 71% vs. 57%. In the cohort of 67 HR patients the CR rate for R+ vs. R- was 81% vs. 88% due to a higher rate of failure/PR 12% vs. 8%. The ED rates in the R+ vs. R- arm were 7% vs. 4%. There was a higher Mol CR rate at wk 16 in the R+ arm vs. R- with 64% vs. 40%. Overall survival for HR patients at 5 yrs was 55% vs. 36% in the R+ vs. R- group. When only the HR cohort with SCT in CR1 is considered (in 69 % +R and 90% -R SCT in CR1 were performed) the CCR probability was superior for the R+ vs. R- with 67% vs. 37%, due to a lower relapse rate. Conclusion: Intensive chemo- plus immunotherapy with Rituximab is feasible in adult patients with B-precursor ALL in the context of the GMALL protocol 07/2003. In standard risk patients, the complete remission rate was comparable. There was however a faster and higher Mol. CR rate in the Rituximab cohort, with an improvement in remission duration and overall survival. In high risk patients the Mol. CR rate was also higher in the R+ arm and the relapse rate after SCT lower, but probably more Rituximab doses are needed in this patient cohort to reduce the tumour load before SCT further. Supported by Deutsche Krebshilfe 70–2657-Ho2 and in part by Hoffmann La Roche. Disclosures: Off Label Use: Rituximab: activity against CD20 pos. ALL cells.

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Efficacy and safety of cladribine: Subcutaneous versus intravenous administration in hairy cell leukemia.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.7013 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 7013-7013

Author(s):

Tarek Yakout Mohamed ◽

Mosaad El Gammal ◽

Alfred Elias Namour ◽

Raafat Ragaie Abdel Malek ◽

Ola Khorshid

Keyword(s):

Complete Remission ◽

Adverse Events ◽

Hairy Cell Leukemia ◽

Route Of Administration ◽

Similar Response ◽

Hairy Cell ◽

Cell Leukemia ◽

Laboratory Parameters ◽

Significant Difference

7013 Background: Hairy cell leukemia (HCL) is rare B-cell lymphoproliferative disorder. Its treatment has evolved from splenectomy with time to failure (TTF) of 19 months to Cladribine that increased complete remission (CR) rate to 90%, with only small percentage of patients relapsing at 30 months. Cladribine (CDA) is originally administered intravenously as continuous infusion for 7 days; Subsequently, it was administered subcutaneously. This study aims at comparing efficacy and toxicity of Subcutaneous (SC) versus Intravenous (IV) administration of CDA in treatment of HCL. Methods: This retrospective study included HCL patients presented to National Cancer Institute and Nasser Institute, Cairo, Egypt, during period 2004-2010. Included patients received CDA as 1st or 2nd line with minimum follow up of 12 months. All files were reviewed for baseline clinical & laboratory parameters, route of administration, response, adverse events and survival. Results: This study included 49 eligible patients, 41 patients received CDA as 1st line treatment, while 8 patients as 2nd line. Eighteen patients were treated by continuous IV infusion whereas 31 patients by SC injections. Both groups were comparable regarding baseline clinical and laboratory parameters with no statistically significant difference. At median follow up period of 33.5 months, complete remission rate was 94% in IV group versus 97% in SC group (p=0.691); median TTF for IV group was 52.9 months while that for SC group was not reached (p=0.035). The median time to achieve CR in both arms was similar. By analyzing different factors affecting TTF using multivariate analysis, route of administration proved to be the only statistically significant factor (P=0.006). Regarding adverse events, there was no difference between both groups in hematological toxicities. IV route was associated with a significant higher incidence of mucositis (p=0.02) and viral infections (p=0.01). Hepatotoxicity and neurotoxicity were higher in SC group but difference was not statistically significant. Conclusions: SC administration of cladribine is an alternative route to IV in treatment of HCL with similar response rate, longer time to treatment failure and better tolerability.

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