Failure of salvage vemurafenib therapy for refractory multisystem Langerhans cell histiocytosis with BRAF-V600E mutation

Background Langerhans cell histiocytosis (LCH) has been defined as a disorder driven by misguided myeloid differentiation, with up to 50% of cases harboring the BRAF-V600E mutation. Salvage treatment with LCH refractory to vinblastine and steroid regimen is intractable. Vemurafenib is safe and effective in children with refractory BRAF-V600E-positive LCH, but the disease always reactivates with the withdrawal of vemurafenib. Case presentation: Here, we report the first case of BRAF-V600E positive LCH resistant to vemurafenib therapy but effectively salvaged by cytarabine-based chemotherapy. Conclusions Our case report shows that vemurafenib monotherapy might not be effective for every BRAF-V600E-positive refractory LCH, and cytarabine-based chemotherapy might still be a cost-effective therapeutic alternative. Keywords: Langerhans cell histiocytosis, BRAF-V600E mutation, Vemurafenib, Chemotherapy

Steroid treatment for the first episode of childhood nephrotic syndrome: comparison of the 8 and 12 weeks regimen using an individual patient data meta-analysis

Steroids are the cornerstone of the treatment of childhood nephrotic syndrome. The optimal duration for the first episode remains a matter of debate. The aim of this study is to determine whether the 8 weeks International Study of Kidney Disease in Children (ISKDC) regimen is equally effective as the 12 weeks steroid regimen from the German society of pediatric nephrology (Arbeitsgemeinschaft für Pädiatrische Nephrologie [APN]). An individual patient data (IPD) meta-analysis of randomized controlled trials reporting on prednisolone treatment for a first episode of childhood nephrotic syndrome was conducted. European trials aimed at investigating the ISKDC and/or APN steroid regimen were selected. The lead investigators of the selected trials were requested to provide the IPD of the specific treatment groups. Four trials included European cohorts using dosing schedules according to the regimens studied. IPD of two trials were available. A significant difference was found in time to first relapse after cessation of steroid treatment between the 8 and 12 weeks treatment group with a median time to relapse of 29 and 63 days, respectively. Moreover, relapse rate ratios during total follow-up were 51% higher for the 8 weeks regimen. Finally, younger children have a significantly lower time to first relapse and frequently relapsing nephrotic syndrome.Conclusions: The results of this IPD meta-analysis suggest that the 8 weeks steroid regimen for a first episode of steroid-sensitive nephrotic syndrome may not be equally effective as the 12 weeks steroid regimen. Moreover, this study highlights the importance of using uniform definitions to enable accurate comparison and interpretation of trial results.Trial registration: Registration number: CRD42020199244, date of registration 16-08-2020 What is Known:• Steroids are the cornerstone of the treatment of childhood nephrotic syndrome, however the optimal duration for the first episode remains a matter of debate.• Currently, the 8 weeks ISKDC protocol and 12 weeks APN protocol are among the most frequently used protocols in Europe. What is New:• The 8 weeks steroid regimen for a first episode of steroid-sensitive nephrotic syndrome may not be equally effective as the 12 weeks steroid regimen for the treatment of a first episode of nephrotic syndrome.• Younger children have a significantly shorter time to first relapse and time to frequent relapsing nephrotic syndrome.

MON-168 Peri-Operative Glucocorticoids in Patients Having Total Joint Replacements: Help or Harm?

Introduction: There is limited evidence to guide peri-operative steroid regimen in patients receiving chronic glucocorticoid (GC) therapy. Many patients who undergo minor surgical procedures receive stress-dose steroids. While hemodynamic instability and hypotension are well-recognized risks of inadequate peri-operative GCs, there may be harms associated with using doses higher than necessary. Whether surgical outcomes differ according to peri-operative steroid dose is not known. We hypothesized that patients who had greater GC exposure have less hypotension, but higher rates of hyperglycemia and post-operative complications. Methods: This retrospective study investigated the relationships between peri-operative GC use and post-operative complications following total hip/knee joint replacement (arthroplasty) in patients with rheumatoid arthritis (RA). All GCs were converted to prednisone equivalents; GC exposure was assessed by number of doses and total cumulative dose during the hospitalization. Complications (infection, thromboembolism and cardiovascular events) were determined by chart review. Results: Of 432 patients with RA included, half (54%) underwent knee arthroplasty. Mean age was 64±12 years, 78% were women. Thirty percent of patients were on home GCs (mean dose 7±4mg/day). Median cumulative GC dose during hospitalization was 37mg [IQR 27, 57]. Compared to patients who only received one peri-operative dose of steroids, those who received multiple doses had a greater risk of post-operative complications (OR 3.319 (95% CI 1.03, 12.62; p<0.05] and hyperglycemia, glucose >180 mg/dl, [OR 1.812(0.99, 3.32; p<0.05]. They did not have an increase in hypotension or need for pressors. Among patients who received steroids while in the hospital (90%), there was a small but significant dose response relationship with hyperglycemia (r=0.16; p<0.01). Higher cumulative dose was also associated with higher risk of complications; for every 10 mg increase in cumulative dose, the risk of complications increased by 15% (p<0.01). Conclusions: Among RA patients undergoing arthroplasty, we did not find that lower doses of GCs were related to more hypotension. However, patients with higher GC exposure were more likely to have hyperglycemia and post-operative complications. Our results suggest that use of peri-operative GC is not without risk, and the lowest doses possible should be considered. Further studies are needed to confirm these findings and to define the optimal dosing strategies for patients receiving peri-operative GCs.

Use of Oral Prednisolone and a 3-Phase Bone Scintigraphy in Patients with Complex Regional Pain Syndrome Type I

To compare the treatment effects of a high-dose and low-dose oral steroid regimen based on changes in the radioisotope uptake ratio (RUR) observed from three-phase bone scintigraphy (TPBS) in patients with complex regional pain syndrome type I (CRPS I), we retrospectively analyzed data of 34 patients with CRPS I from traumatic brain injury and stroke. Depending on the dose of steroid administered, patients were divided into high-dose (n = 14) and low-dose steroid groups (n = 20). We compared the severity scores, Kozin’s classification scores, and RUR observed from TPBS between the two groups. There were significant changes in the severity scores and Kozin’s classification between the baseline and 2 weeks from baseline (p < 0.05), however, there were no significant differences in terms of changes in the scores, classification, or the RUR observed from TPBS at 2 weeks from baseline (p > 0.05). There were no treatment-emergent adverse events (TEAEs) such as blood pressure elevation, impaired glycemic control, or gastrointestinal disturbances. Our results indicate that the efficacy profile of a low-dose oral steroid regimen is comparable to that of a high-dose regimen in alleviating symptoms in CRPS I patients. However, additional prospective, large-scale, multi-center studies are warranted to confirm our results.

Stricture Prevention after Extensive Endoscopic Submucosal Dissection of Neoplastic Barrett’s Esophagus: Individualized Oral Steroid Prophylaxis

Introduction. Endoscopic resection (ER) exceeding ≥75% of the esophageal circumference is accompanied with a high stricture risk regardless of the resection method. The ideal strategy for stricture prevention is not well defined today. Different approaches have been reported but data are limited to the resection of squamous cell neoplasia. The aim of this study was to assess the efficacy of an individualized oral steroid regimen to prevent strictures after extensive ER in neoplastic Barrett’s esophagus (NBE). Materials and Methods. Over a 50-month period, endoscopic submucosal dissection (ESD) was performed in 193 patients with NBE. 23 patients with resections exceeding 75% of the circumference were included. 19 resection ulcers were noncircumferential (NCR) while 4 were circumferential (CR). Stricture prevention was performed using oral prednisolone starting with a daily dose of 50 mg and standard tapering over 8 weeks (50/40/30/25/20/15/10/5 mg). Tapering was individualized according to the ulcer healing process (assessed endoscopically in the first tapering period and before stopping the steroids). Data were analyzed retrospectively. Results. Stricture rates were 5.3% (1/19) for NCR and 100% (4/4) for CR (p<0.001). The only stricture in the NCR group was seen in a patient who had stopped steroids without any reason after few days. 12/19 patients received standard tapering over 8 weeks (63.1%). According to the individual ulcer healing, treatment was prolonged to 9-10 weeks in 4/19 (21.1%) and shortened to 7 weeks in another 2/19 (10.5%). After CR, all patients needed endoscopic balloon dilatation (median 6.5 sessions; range 3-14 sessions for 8-40 weeks). Side effects of the steroid therapy were not noted. Conclusion. Oral prednisolone therapy with an endoscopy-based individualized tapering regimen is effective in avoiding strictures after NCR of Barrett’s neoplasia. After CR, the stricture risk is not sufficiently decreased. CR should be restricted to circumferential neoplasia which is a very rare scenario in neoplastic BE.

Short-Term Steroid Regimen for Adult Steroid-Sensitive Minimal Change Disease

Background: In pediatric patients with steroid-sensitive nephrotic syndrome, recent trials have revealed that a 2-month, short-term steroid regimen is not inferior to an extended steroid course. However, the optimal duration of initial steroid therapy for adult steroid-sensitive minimal change disease (MCD) remains unclear. Objectives: The aim of present study was to evaluate the effectiveness of a 2-month, short-term steroid regimen in the treatment of adult steroid-sensitive MCD patients. Method: This was a prospective observational study. Adult patients with steroid-sensitive MCD (n = 35) who were initiated on a short-term steroid regimen between January 2015 and June 2016 were included. The details of the regimen are as follows: (1) prednisolone was administered at an initial dose of 0.8–1.0 mg/kg/day and continued for 4–6 weeks and (2) dosage was reduced to 0.5–0.6 mg/kg/alternate day and continued for 4 weeks. Control patients (n = 140), who were treated using conventional steroid administration, were selected from our previous adult MCD cohort. All patients fulfilled the following criteria: biopsy-proven MCD, age ≥20 years, first episode of nephrotic syndrome, and attainment of complete remission within 4 weeks. The following parameters of patients who received short-term treatment regimen and control patients were compared: any relapse and frequent relapse, adverse events caused by steroid treatment and cumulative steroid dose. Results: Throughout the observation period (median: 17.3 months), 24 (68.6%) patients in the short-term group developed at least one relapse. The short-term regimen showed earlier occurrence of any relapse than the conventional regimen (adjusted hazard ratio [aHR] 2.45; 95% CI 1.51–3.97; p < 0.001), but there was no difference in frequent relapse (aHR 1.31; 95% CI 0.43–3.99; p = 0.63). None of the patients showed any symptoms of adrenal insufficiency after discontinuation of corticosteroids. The cumulative steroid dose during the observational period was significantly lower in the short-term group than in the conventional group. Conclusions: The short-term steroid regimen may represent an effective treatment option that ensures lower steroid exposure when treating adult steroid-sensitive MCD patients.

Pulsed Vincristine Therapy in Steroid-Resistant Nephrotic Syndrome

Steroid-resistant nephrotic syndrome (SRNS) poses a therapeutic challenge for the paediatric nephrologist. As relentless progression to renal failure occurs with continued proteinuria, such patients will be treated with different cytotoxic medications with variable success rates and side-effects. We present here our findings on administering the anticancer drug vincristine for SRNS patients at a single centre in Sri Lanka. Methods. Between 2002 and 2007, fifty-four children presenting with steroid and cyclophosphamide resistance were treated with vincristine at 1.5 mg/m2 in weekly intravenous pulses for 8 weeks along with a tapering steroid regimen of 6 months. All patients were closely followed up for 5 years. Results. Of the 54 patients 39 were males and 15 were females (age range 3.5–11.6 years, median 6.1 years). At the end of the treatment course, 21 patients achieved complete remission while 7 had partial remission and no response was seen in 26 patients. Sustained remission at 6, 12, 24, and 60 months were 15 (27.78%), 11 (20.37%), 9 (16.67%), and 7 (12.96%), respectively. Most side-effects observed were reversible and no serious side-effects were noted during vincristine therapy. Conclusion. Although its therapeutic mechanisms in nephrotic syndrome are still not elucidated, vincristine appears to be a potent alternative that could be considered for treating SRNS.

Response to First Line Treatment in Childhood ITP

Background Immune thrombocytopenia is an idiopathic disorder of platelet destruction, characterised by mucocutaneous bleeding episodes and platelet count <100x109/L. The majority of paediatric patients will spontaneously recover with conservative management. A minority require treatment for bleeding, usually occurring at a platelet count of <20x109/L. Objective Comparison of patient groups by: treatment received, demographics, presentation, disease phase and time to platelet count >50x109/L. Method 1043 patients were identified from the UKITP Registry data from January 2007-May 2016 Results 798 patients were untreated other than supportive care. 245 patients (23%) had 422 treatment episodes for bleeding episodes. 42% of these were clinically mild (grade 1), 51% moderate (grade 2) and 7% severe (grade 3) or life-threatening (grade 4). 15% of patients with mild bleeding received treatment, 35% moderate, 84% severe and 100% life-threatening. 2 patients had intracranial bleeding. The clinical severity of bleeding is positively associated with number of bleed sites. The untreated group were on average older, with a higher platelet count and milder presentation. 136 treatments were with IVIG, 92 steroid 1-2mg/kg/day (Regimen 1) and 60 with steroid 4mg/kg/day for 4 days (Regimen 2). 71 treatments were with combination therapy. No significant difference was found between platelet count of treated and untreated groups over first 3 months Regimen 2 produce a faster, but transient rise in platelet count compared to Regimen 1. Steroids were more likely to be used for mouth bleeding and menorrhagia compared to IVIG and combination therapy. Lower GI bleeds demonstrate more IVIG and combination therapies. Macroscopic haematuria cases received more steroid Regimen 1 than other therapies. With increasing duration of disease the frequency of treatment was reduced from 261 treatments per 100 days (newly diagnosed) to 3 treatments per 100 days (chronic disease). The greatest platelet increase was observed following IVIG or combination therapy with a median platelet count 37x109/L by day 3 (IVIG) and 43x109/L (combination) and 61x109/L by day 5 (IVIG) and 90x109/L (combination). A median platelet count maintained >30x109/L to week 6 (IVIG) and week 8 (combination). In contrast both steroid regimens took until d5 to achieve a platelet response which was maintained until week 4 (regimen 1) and week 6 (regimen 2). Conclusion Currently 23% of children with ITP are receiving treatment in the UK. A higher proportion required treatment with increasing bleeding severity and number of bleeding sites. IVIG demonstrated a superior response to steroid therapy and should be considered preferable for more significant bleeding. A higher dose, short duration steroid regimen was associated with a better response compared to lower dose treatment and is preferable for milder bleeding that requires therapy. Disclosures Grainger: GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bolton-Maggs:Novartis: Honoraria; Grifols: Honoraria.