Deferasirox (Exjade®), the Once-Daily Oral Iron Chelator, Demonstrates Safety and Efficacy in Patients with Sickle Cell Disease (SCD): 3.5-Year Follow-up.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1420-1420 ◽  
Author(s):  
Elliott Vichinsky ◽  
Thomas Coates ◽  
Alexis A Thompson ◽  
Françoise Bernaudin ◽  
Martha Rodriguez ◽  
...  
Keyword(s):  
Renal Function ◽  
Iron Overload ◽  
Iron Concentration ◽  
Transfusion Therapy ◽  
Safety And Efficacy ◽  
To Receive ◽  
Dose Dependent ◽  
Median Change

Abstract Background: Many patients with SCD require chronic transfusion therapy to manage the complications of their disease (eg stroke prevention); as a consequence, secondary iron overload may develop. Controlled data from patients with SCD receiving long-term iron chelation therapy, particularly renal function, are lacking. Cumulative 3.5-year safety and efficacy data are presented for adult and pediatric patients with SCD with transfusional iron overload treated with deferasirox (Exjade®) in a 4-year extension to a 1-year comparative study (109). Methods: Study 109 demonstrated similar dose-dependent liver iron concentration (LIC) reductions with deferasirox and deferoxamine (DFO) in SCD patients with iron overload. Eligible patients entered a 4-year extension phase and received deferasirox only; dose adjustments were based on monthly serum ferritin (SF) levels and safety assessments (adverse events [AEs] and laboratory parameters). Patients with abnormal renal function were excluded. Results: 132 patients (mean age ± SD of 19.1 ± 10.7 years) who were initially randomized in the core study to receive deferasirox are included in this analysis. The median duration of exposure to deferasirox was 37.4 months (3.1 years) at a mean dose of 18.4 ± 6.2 mg/kg/day. Mean iron intake over this period was 0.3 ± 0.1 mg/kg/day. 72 patients (54.5%) continue to receive deferasirox. Reasons for discontinuations include: AEs (n=11), consent withdrawal (n=24), lost to follow-up (n=9), unsatisfactory therapeutic effect (n=4), and other reasons (n=11). There was also one death reported post-liver transplantation, which was not considered by the investigator to be related to the study drug. The most frequent drug-related (investigator-assessed) AEs were nausea (n=20; 15.2%), diarrhea (n=14; 10.6%), vomiting (n=8; 6.1%) and abdominal pain (n=6; 4.5%). Nine patients (6.8%) had two consecutive increases in serum creatinine that were both >33% above baseline and above the upper limit of normal (ULN); however, there were no progressive increases. Five patients (3.8%) had an increase in alanine aminotransferase >10xULN on at least one visit; baseline levels were already >ULN in two patients. Mean daily dose of deferasirox increased from 15.4 ± 6.9 mg/kg/day at month 1 to 22.3 ± 7.3 mg/kg/day at month 42. Overall baseline median SF level was 3439 ng/mL (n=132), which decreased by 651 ng/mL (P=0.0533, Wilcoxon signed rank test; n=49) by month 42 (Figure 1). SF decreases were dose-dependent (data not shown). Figure 1. Mean dose and median change in SF during deferasirox treatment Figure 1. Mean dose and median change in SF during deferasirox treatment Conclusions: Patients with SCD and transfusional iron overload receiving long-term deferasirox demonstrated continued reduction in their body iron burden (according to SF levels), without an exposure-associated increase in AE incidence, or evidence of progressive renal dysfunction.

Long Term Efficacy, Safety and Tolerability (>24 Months) of Twice Daily Dosing of Deferasirox in Transfusion Dependent Thalassemias Who Were Unresponsive to Standard Once Daily Dose

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 958-958
Author(s):  
Bunchoo Pongtanakul ◽  
Vip Viprakasit
Keyword(s):  
Iron Overload ◽  
Iron Concentration ◽  
Iron Chelation ◽  
Once Daily ◽  
Term Efficacy ◽  
Before And After ◽  
Baseline Levels ◽  
Median Change

Background: Clinical efficacy, safety and tolerability of deferasirox (DFX); a once daily oral iron chelator in transfusion dependent thalassemias (TDT) with iron overload can be achieved by appropriate dosage adjustment based on iron burden and ongoing transfusion iron overload. However, even with recommended DFX dosage, at least 40% of our Thai TDT patients did not appropriately respond to DFX. Patients with unresponsiveness to DFX (UR) was defined as (1) having a rising serum ferritin (SF) trend or (2) having a reduction of SF < 30% of baseline levels (BL) at least 3 consecutive mths, with more than two SF measurements >1500 ng/mL; and (3) receiving once daily DFX at an average dosage > 30 mg/kg/day for at least 6 mths. Previously, twice daily dosing (TWD) of DFX was shown to be effective in patients with UR (Pongtanakul B, et al. Blood Cells Mol Dis. 2013) but long term efficacy, safety and tolerability of TWD of DFX is still lacking. Methods: Patients with UR who received TWD of DFX with the same total dose per day > 24 mths were included. CBC, renal function, urine analysis were performed every 3 wks to monitor possible side effect. SF and liver function test were checked every 6 wks. Tolerability and compliance to DFX were evaluated by direct history taking and drug account prescribed. Responsiveness to TWD of DFX (RP) was defined as the patients who showed a decrease of SF or reduction of liver iron concentration (LIC) by MRI > 30% of the BL at 6 or 12 mths. Results: Twenty four TDT patients received TWD of DFX; 4 patients were excluded due to poor compliance and a short follow up period and 4 patients did not meet RP criteria. Sixteen patients were enrolled; 9 male (56%) with a mean (± SD) age of 9.08 ± 3.84 yrs (range 2.1-24.2 yrs). Clinical diagnoses include; Hb E/β thalassemia. (n=12), β thalassemia major (n=3) and Hb Barts hydrops (n=1). Mean follow up time before switching dose were 17.3 ± 7.3 mths. Average SF at BL before DFX and before TWD were 3,039 ± 1,713.7.02 and 3,500 ± 1,403.2 ng/mL, with median % change of SF was +27.58 % (range; -13.4 to +104%). Mean actual DFX dose during 6 mths before switching was 36.3 ± 2.2 mg/kg/day. None had symptoms of gastrointestinal irritation. After TWD, 13 (81.25%) and 16 patients (100%) showed a significant decrease of SF (> 30% of the baseline levels) at 6 and 12 months. Mean SF and median % change of SF at 6 and 12 months after switching were 2,527.56 ± 1,191.80 ng/mL; -29.24 % and 1,695.83 ± 859.16 ng/mL; -53.14%, with statistical significance compared to BL and before switching (p <0.05). Mean transfusion iron load before and after switching were not different (range 0.2-0.4 mg/kg/day). One patient had a SF reduction < 30%, but LIC was significant reduction at 12 months. Nine out of 16 patients were evaluated for LIC; average LIC at BL and at the end of study were reduced from 6.7 to 3.2 mg/g dry wt. None had cardiac T2* < 20 msec. All patients except one tolerated well with DFX at before and after switching (>24 months) with minor adverse events. One patient had severe transaminitis (ALT > 3 times of ULN) but after investigation, this was thought to be result from acute viral hepatitis. This patient could be successfully restarted DFX at the same TWD. Five patients could decrease DFX dosage to < 20 mg/kg/day and switched back to daily dosing (mean dosage was 17.04 mg/kg/day). However, 4 patients, after decreased DFX dosage and switched back to daily dosing; their SF increased and required to increase DFX dosage with TWD to maintain SF. Seven patients continued to receive TWD of DFX with mean dosage was 36.4 mg/kg/day. Mean follow up time after TWD of DFX was 44.1 + 9.8 mths (range 24 - 72 mths). Conclusion: Herein, we show that TWD of DFX effectively reduced iron burden in TDT with iron overload. Safety and tolerability of this dosing are not different from once daily dosing. Most patients could decrease DFX dosage and switched back to once daily dosing when iron burden decreased. However, 25% (4/16) of these patients still required twice daily dosing with higher dosage to maintain optimal body iron levels. Interestingly, 16% (4/24) of our patients who received TWD could not achieve effective iron chelation. This group of patients may represent those who have different pharmacogenetic background that affect directly to efficacy of DFX causing a resistant to iron chelation therapy. This population confirms for improving iron chelation measures by means of a newer iron chelation agent or a combination of DFX with other iron chelation. Disclosures Off Label Use: Twice daily dosing instead of standard daily dosing.

scholarly journals Effects of renal denervation on kidney function and long-term outcomes: 3-year follow-up from the Global SYMPLICITY Registry

2019 ◽  
Vol 40 (42) ◽  
pp. 3474-3482 ◽  
Author(s):  
Felix Mahfoud ◽  
Michael Böhm ◽  
Roland Schmieder ◽  
Krzysztof Narkiewicz ◽  
Sebastian Ewen ◽  
...  
Keyword(s):  
Renal Function ◽  
Real World ◽  
Active Sites ◽  
Renal Denervation ◽  
Uncontrolled Hypertension ◽  
Open Label ◽  
Hypertensive Patients ◽  
Safety And Efficacy

Abstract Aims Several studies and registries have demonstrated sustained reductions in blood pressure (BP) after renal denervation (RDN). The long-term safety and efficacy after RDN in real-world patients with uncontrolled hypertension, however, remains unknown. The objective of this study was to assess the long-term safety and efficacy of RDN, including its effects on renal function. Methods and results The Global SYMPLICITY Registry is a prospective, open-label registry conducted at 196 active sites worldwide in hypertensive patients receiving RDN treatment. Among 2237 patients enrolled and treated with the SYMPLICITY Flex catheter, 1742 were eligible for follow-up at 3 years. Baseline office and 24-h ambulatory systolic BP (SBP) were 166 ± 25 and 154 ± 18 mmHg, respectively. SBP reduction after RDN was sustained over 3 years, including decreases in both office (−16.5 ± 28.6 mmHg, P < 0.001) and 24-h ambulatory SBP (−8.0 ± 20.0 mmHg; P < 0.001). Twenty-one percent of patients had a baseline estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. Between baseline and 3 years, renal function declined by 7.1 mL/min/1.73 m2 in patients without chronic kidney disease (CKD; eGFR ≥60 mL/min/1.73 m2; baseline eGFR 87 ± 17 mL/min/1.73 m2) and by 3.7 mL/min/1.73 m2 in patients with CKD (eGFR <60 mL/min/1.73 m2; baseline eGFR 47 ± 11 mL/min/1.73 m2). No long-term safety concerns were observed following the RDN procedure. Conclusion Long-term data from the Global SYMPLICITY Registry representing the largest available cohort of hypertensive patients receiving RDN in a real-world clinical setting demonstrate both the safety and efficacy of the procedure with significant and sustained office and ambulatory BP reductions out to 3 years.

Twice Daily Dosing of Deferasirox Significantly Improves Clinical Efficacy in Transfusion Dependent Thalassemias Who Were Inadequate Responders to Standard Once Daily Dose

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1026-1026
Author(s):  
Bunchoo Pongtanakul ◽  
Vip Viprakasit
Keyword(s):  
Iron Overload ◽  
Clinical Efficacy ◽  
Drug Exposure ◽  
Iron Concentration ◽  
Once Daily ◽  
Daily Dose ◽  
Before And After ◽  
Baseline Levels ◽  
Median Change

Abstract Abstract 1026 Background: Clinical efficacy of deferasirox (DFX); a once daily oral iron chelator in patients with transfusional iron overload depends on factors such as iron burden, rate of transfusion and appropriate dose. At present, the recommended dose approved as a label indication is 30 mg/kg/day, though doses up to 40 were studied in patients with cardiac siderosis with acceptable safety profiles. Recent several studies have shown in a non-clinical trial setting that a proportion of patients could not achieve satisfactory iron balance at 30 mg/kg/day or even at higher dose. These patients were labeled as inadequate responder (IR). In our center, surprisingly 44.2% of transfusion dependent thalassemia patients were classified as IR to DFX since the drug was registered in 2007. Difference in bioavailability with a lower area under the curve (AUC) of each IR individual was the only main mechanism identified earlier (Neufeld E, et al. Blood 2009). We hypothesize that adjusting DFX dose from once daily into two dividing dose per day might improve drug exposure and chelating efficacy in such patients. Methods: Patients with IR was primarily defined as (1) having a rising serum ferritin (SF) trend or (2) having a reduction of SF less than 30% of baseline levels (BL) at least 3 consecutive months, with more than two SF measurements higher than 1500 ng/mL; and (3) receiving once daily DFX at an average dosage > 35 mg/kg/day for at least 6 months. DFX administration schedule was switched to twice daily with the same total dose per day. CBC, renal function, urine analysis were performed every 3 weeks to monitor possible adverse effects. SF and liver function test were checked every six weeks. Tolerability and compliance to DFX were evaluated by direct history taking and drug account prescribed during study period. Results: Nineteen patients were met inclusion criteria; 2 patients were excluded from further study due to poor compliance and a short follow up period. Total 17 patients (7 male, 41%) were eligible with a mean (± SD) age of 10.22 ± 4.1 yrs (range; 2.1–18 yrs). Clinical diagnoses include; Hb E/β thal. (n=13), β thal. major (n=3) and Hb Barts hydrops (n=1). Mean follow up time before and after switching dose admin were 15.3 ± 6.3 and 20.8 ± 10.3 mths. Average SF at baseline (BL) before DFX and before switching regimen were 3,632 ± 2,031.02 and 3,844 ± 2,144.3 ng/mL, respectively with median % change of SF was +15.8 % (range; −29.8 to +104%). Mean actual DFX dose during 6 mths before switching was 37.22 ± 2.3 mg/kg/day. None of studied patients was DFX intolerance as they had no symptoms of gastrointestinal (GI) irritation. After twice daily dose, 10 (58.8%) and 14 patients (82.4%) showed a significant decrease of SF (> 30% of the baseline levels) at 6 and 12 mths. Mean SF and median % change of SF at 6 and 12 months after switching were 2,380.53 ± 1,774.62 ng/mL; −38.08 % and 1,588.12 ± 1,373.22 ng/mL; −58.7%, respectively with statistical significance compared to BL and before switching (p <0.05). Mean transfusion iron load before and after switching were not different (range 0.2–0.4 mg/kg/day). Although 3 patients had a SF reduction < 30%, all showed a reducing trend; −11.5%, −25.7% and −25.6% at 12 mths. Five from 17 patients were evaluated for liver iron concentration (LIC); average LIC at BL and at the end of study (EOS) were significantly reduced from 11.2 to 5.85 mg/g dry wt. None had cardiac T2* < 20 msec. All patients except two tolerated well with DFX at before and after switching (up to 12 months) with minor adverse events (AEs). One patient had significant proteinurea after 6 months and one with severe transaminitis (ALT > 3 times of ULN). They were temporarily discontinued with DFX and both AEs were completely resolved and did not recur when they were resumed on the twice daily regimen. Conclusion: Previously, twice daily DFX was shown to be effective in patients with DFX intolerance. We show herein that patients with IR might also be beneficial from a twice daily dosing with clinically well-tolerance and acceptable compliance. Dividing DFX into twice daily dose might provide a better bioavailability in selected patients with sustainable therapeutic levels of DFX throughout 24 hr-exposure resulting in a better clinical efficacy. Further pharmacokinetic and pharmacogenetic study in IR patients is warranted and this can provide additional insights on the next level of tailoring iron chelation therapy in patients with transfusional iron overload. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Carbon ion radiotherapy for prostate cancer with bladder invasion

BMC Urology ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yuhei Miyasaka ◽  
Hidemasa Kawamura ◽  
Hiro Sato ◽  
Nobuteru Kubo ◽  
Tatsuji Mizukami ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Locally Advanced ◽  
Therapeutic Benefit ◽  
Carbon Ion Radiotherapy ◽  
Safety And Efficacy ◽  
Carbon Ion ◽  
Grade 3 ◽  
Bladder Invasion

Abstract Background The optimal management of clinical T4 (cT4) prostate cancer (PC) is still uncertain. At our institution, carbon ion radiotherapy (CIRT) for nonmetastatic PC, including tumors invading the bladder, has been performed since 2010. Since carbon ion beams provide a sharp dose distribution with minimal penumbra and have biological advantages over photon radiotherapy, CIRT may provide a therapeutic benefit for PC with bladder invasion. Hence, we evaluated CIRT for PC with bladder invasion in terms of the safety and efficacy. Methods Between March 2010 and December 2016, a total of 1337 patients with nonmetastatic PC received CIRT at a total dose of 57.6 Gy (RBE) in 16 fractions over 4 weeks. Among them, seven patients who had locally advanced PC with bladder invasion were identified. Long-term androgen-deprivation therapy (ADT) was also administered to these patients. Adverse events were graded according to the Common Terminology Criteria for Adverse Event version 5.0. Results At the completion of our study, all the patients with cT4 PC were alive with a median follow-up period of 78 months. Grade 2 acute urinary disorders were observed in only one patient. Regarding late toxicities, only one patient developed grade 2 hematuria and urinary urgency. There was no grade 3 or worse toxicity, and gastrointestinal toxicity was not observed. Six (85.7%) patients had no recurrence or metastasis. One patient had biochemical and local failures 42 and 45 months after CIRT, respectively. However, the recurrent disease has been well controlled by salvage ADT. Conclusions Seven patients with locally advanced PC invading the bladder treated with CIRT were evaluated. Our findings seem to suggest positive safety and efficacy profiles for CIRT.

scholarly journals Renal function following acute renal failure in childhood: A long term follow-up study

1989 ◽  
Vol 35 (1) ◽  
pp. 84-89 ◽  
Author(s):  
Helen N. Georgaki-Angelaki ◽  
David B. Steed ◽  
Cyril Chantler ◽  
George B. Haycock
Keyword(s):  
Renal Failure ◽  
Renal Function ◽  
Acute Renal Failure ◽  
Follow Up Study ◽  
Long Term Follow Up

Long-term follow-up of renal function in patients after surgery for obstructive uropathy

2008 ◽  
Vol 23 (6) ◽  
pp. 937-945 ◽  
Author(s):  
Daniela Miklovicova ◽  
Olga Cervenova ◽  
Andrea Cernianska ◽  
Zuzana Jancovicova ◽  
Ladislav Dedik ◽  
...  
Keyword(s):  
Renal Function ◽  
Obstructive Uropathy ◽  
Long Term Follow Up

Nivolumab (NIVO) plus ipilimumab (IPI) versus chemotherapy (chemo) as first-line (1L) treatment for advanced non-small cell lung cancer (NSCLC): 4-year update from CheckMate 227.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9016-9016
Author(s):  
Luis G. Paz-Ares ◽  
Tudor-Eliade Ciuleanu ◽  
Jong-Seok Lee ◽  
Laszlo Urban ◽  
Reyes Bernabe Caro ◽  
...  
Keyword(s):  
Advanced Nsclc ◽  
Performance Status ◽  
Stage Iv ◽  
Ecog Performance Status ◽  
Programmed Death ◽  
Long Term Follow Up ◽  
To Receive ◽  
Clinical Trial Information

9016 Background: 1L NIVO + IPI was shown to provide durable long-term overall survival (OS) benefit vs chemo regardless of tumor programmed death ligand 1 (PD-L1) expression in patients (pts) with advanced NSCLC in CheckMate 227 Part 1 (NCT02477826); 3-year OS rates were 33% vs 22% in pts with PD-L1 ≥ 1% (HR, 0.79 [95% CI, 0.67–0.93]) and 34% vs 15% in pts with PD-L1 < 1% (HR, 0.64 [95% CI, 0.51–0.81]). Here we report updated results from the study with 4 years’ minimum follow-up. Methods: Adults with previously untreated stage IV / recurrent NSCLC, no known EGFR/ ALK alterations , and ECOG performance status ≤ 1 were enrolled; pts were stratified by squamous (SQ) and non-squamous (NSQ) histology. Pts with PD-L1 ≥ 1% (n = 1189) were randomized 1:1:1 to receive NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W), NIVO alone (240 mg Q2W), or chemo. Pts with PD-L1 < 1% (n = 550) were randomized 1:1:1 to receive NIVO + IPI, NIVO (360 mg Q3W) + chemo, or chemo. OS with NIVO + IPI vs chemo in pts with PD-L1 ≥ 1% was the primary endpoint. Results: With minimum follow-up of 49.4 months (database lock, Feb 18, 2021), pts were at least 2 years beyond the protocol-specified end of immunotherapy treatment. Pts with PD-L1 ≥ 1% continued to show durable benefit with NIVO + IPI vs chemo (HR, 0.76 [95% CI, 0.65–0.90]); 4-year OS rates were 29% (NIVO + IPI), 21% (NIVO), and 18% (chemo). At 4 years, 14% (NIVO + IPI), 10% (NIVO), and 4% (chemo) remained progression free. Among responders, 34%, 30%, and 7% remained in response, respectively. In an exploratory analysis in pts with PD-L1 ≥ 50%, 4-year OS rates were 37% (NIVO + IPI), 26% (NIVO), and 20% (chemo). In pts with PD-L1 < 1%, OS HR for NIVO + IPI vs chemo was 0.64 (95% CI, 0.51–0.81); 4-year OS rates were 24% (NIVO + IPI), 13% (NIVO + chemo) and 10% (chemo). At 4 years, 12% (NIVO + IPI), 7% (NIVO + chemo), and 0% (chemo) remained progression free. Among responders, 31%, 13%, and 0% remained in response, respectively. Among pts who progressed on NIVO + IPI vs chemo, 7% vs 40% (PD-L1 ≥ 1%), and 9% vs 33% (PD-L1 < 1%), received subsequent immunotherapy. Benefit with NIVO + IPI vs chemo was observed for both SQ and NSQ histology (Table). With long-term follow-up, no new safety signals were identified. Conclusions: With 4 years’ minimum follow-up, 1L NIVO + IPI continued to provide durable, long-term OS benefit vs chemo in pts with advanced NSCLC regardless of PD-L1 expression or histology. Clinical trial information: NCT02477826. [Table: see text]

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