Low-dose Maintenance Research Articles

SUN-420 Spontaneous Changes in TSH Levels After Thyroidectomy During Long-Term Follow-Up

Background. Spontaneous serum TSH variations during levothyroxine replacement therapy and multiple dose changes in athyreotic patients seem to be frequent in clinical practice. Aim. To describe the rate and extent of spontaneous serum TSH variations in patients after total thyroidectomy for differentiated thyroid cancer (DTC) in real-life practice, and the number of resulting levothyroxine (LT4) dose adjustments. Methods. Data of DTC patients were prospectively collected at a single referral center between January 2005 and May 2019. TSH and fT4 serum levels, LT4 dose and formulation, and concomitant medications were recorded at 1, 3, and 12 months after primary treatment (surgery ± radioiodine therapy), and then yearly; the data were retrospectively evaluated for this study. Visit at one month was used to tailor LT4 dose and was not considered into the data analysis. Patients with structural evidence of disease or during pregnancy were excluded. Results. Data of 2883 evaluations (472 patients) were collected; at baseline, the median age was 49.7 years, 73.5% were females. The LT4 formulation administered at baseline were tablets (84.9%), liquid solution (11.4%), or soft-gel capsule (3.7%). Overall, in 27.5% of clinical evaluation with unchanged levothyroxine dose (341/1243), there were meaningful spontaneous TSH variations (defined as delta TSH > 1.5 mcUI/ml) at yearly follow-up visit. It is clinically significant: in 6.6% of visits, overt thyrotoxicosis was recorded. Furthermore, the treating clinicians decided to change the LT4 dose in 37.1% of cases. These figures were not significantly higher in the first years, and a rate above 25% persist even after ten years of follow-up. The median maintenance dose needed was 1.61 (interquartile range [IQR] 1.41-1.92) mcg/Kg/day for tablets, 1.54 (IQR 1.39-1.79) mcg/Kg/day for liquid solution, and 1.46 (IQR 1.23-1.71) mcg/Kg/day for soft-gel capsules. After correction for daily dose, there was no difference in the rate of TSH variations > 1.5 mcUI/ml, or in the absolute value of median delta of TSH between the three formulations. In 20.1% of patients, the LT4 formulation was changed during the follow-up: it was more common in patients with a known gastroenteric disease (OR 1.76, p=0.03). Conclusions. TSH spontaneous variations and dose adjustments are very common in patients after total thyroidectomy, even during long-term follow-up: wide variations happen in more than 1/4 of all visits, and dose changes are needed in more than 1/3 of all evaluations. We were more inclined to change LT4 formulation in patients with known interference in LT4 absorption: however, no difference in TSH variations was recorded between users of three different formulations, even if soft-gel capsules seem to have a lower maintenance dose.

Amiodarone-induced vortex keratopathy at a low maintenance dose

Vortex keratopathy is a common side effect of amiodarone, which is a class III antiarrhythmic agent. We describe a 50-year-old man who developed vortex keratopahy with amiodarone 200 mg BD for atrial fibrillation since two years. The daily (400 mg/day) and cumulative dose (100 g) combined with the length of therapy is associated with the toxicity. Toxic effects may also be observed at lower maintenance doses, as observed in this patient. This case indicates that multi-organ toxicity due to amiodarone may develop even with short-term use and a low maintenance dose. Having been off the medication for two months, it is expected that the deposition pattern will diminish, as is the case for the vast majority of patients.

Type B insulin resistance syndrome in a patient with type 1 diabetes.

SummaryType B insulin resistance syndrome (TBIRS) is a very rare autoimmune disorder with polyclonal autoantibodies against the insulin receptor, resulting in severe and refractory hyperglycemia. Described here is a patient who within a few months after the onset of autoimmune type 1 diabetes increased her insulin requirements more than 20-fold; despite this she had considerable difficulty maintaining a plasma glucose value of <40–60 mmol/L (720–1100 mg/dL). On suspicion of TBIRS, the patient was started on tapering dose of glucocorticoids to overcome the autoimmune insulin receptor blockade, resulting in an immediate and pronounced effect. Within days, insulin requirements decreased by 80–90% and plasma glucose stabilized around 7–8 mmol/L (126–144 mg/dL). The presence of antibodies to the insulin receptor was detected by immunoprecipitation and binding assays. After a 4-month remission on low maintenance dose prednisolone, the patient relapsed, which required repeated plasmaphereses and immune column treatments with temporarily remarkable effect. Mixed and transient results were seen with rituximab, mycophenolic acid and bortezomib, but the glycemic status remained suboptimal. Lack of compliance and recurrent infections may have contributed to this.Learning points:Type B insulin resistance syndrome (TBIRS) is a very rare autoimmune disorder with acquired polyclonal autoantibodies against the insulin receptor, resulting in severe and refractory hyperglycemia.We describe here a young patient in whom, a few months after the onset of a regular autoimmune diabetes, insulin requirements in a short time increased more than 20-fold, but despite this, the plasma glucose level could be kept at <40–60 mmol/L only with considerable difficulty. Did this patient have TBIRS?On suspicion of TBIRS, the patient was started on tapering glucocorticoids to overcome the autoimmune insulin receptor blockade, resulting in an immediate and pronounced effect; within days insulin requirements decreased by 80–90% and plasma glucose stabilized around 7–8 mmol/L.The presence of antibodies to the insulin receptor was detected by immunoprecipitation and binding assays.After a 4-month remission on low maintenance dose prednisolone, the patient relapsed, which required repeated plasmaphereses with temporarily remarkable effect.TBIRS should be considered in diabetic patients whose glycemia and/or insulin requirements are inexplicably and dramatically increased.

Quadritherapy vs standard tritherapy immunosuppressant regimen after heart transplantation: A propensity score-matched cohort analysis.

After heart transplant, adding everolimus (EVL) to standard immunosuppressive regimen mostly relies on converting calcineurin inhibitors (CNIs) into EVL. The aim of this study was to describe the effects of combining low-dose EVL and CNIs in maintenance immunosuppression regimen (quadritherapy) and compare it with standard tritherapy associating standard-dose CNIs, mycophenolate mofetil, and corticosteroids. In the 3-year registry cohort of heart transplanted patients, those who received quadritherapy were compared with those who received tritherapy. EVL was added after 3months posttransplant. Three analyses were performed to control for confounders: propensity score matching, multivariable survival, and inverse probability score weighting analyses. Among 213 patients who were included (75 with quadritherapy), propensity score matching selected 64 unique pairs of patients with similar characteristics. In the matched cohort (n=128), quadritherapy was associated with fewer deaths (3 [4.7%] vs 17 [21.9%], P=.007) and biopsy-proven acute rejections (15 [23.4%] vs 31 [48.4%], P=.002). These results were confirmed in the overall cohort (n=213), after multivariable and inverse probability score weighting analyses. Renal function and donor-specific HLA-antibodies remained similar in both groups. Low-dose combination quadritherapy was associated with fewer deaths and rejections, compared with standard immunosuppression tritherapy.

Weaning Immunosuppressant in Patients with Failing Kidney Grafts and The Outcomes: A Single-Center Retrospective Cohort Study

An immunosuppressant weaning protocol in failing allografts has not yet been established. Maintaining immunosuppressants would preserve residual renal function (RRF) and prevent graft intolerance syndrome and sensitization but would increase the risks of infection and malignancy. In this study, graft failure cases after kidney transplantation in a single center were reviewed retrospectively. The outcome differences in all-cause mortality, infection-related hospitalization, cancer, graft intolerance syndrome, re-transplantation, and RRF duration between the immunosuppressant maintaining and weaning groups 6 months after graft failure were compared. Among the weaning group, the outcome differences according to low-dose steroid use were also compared at 6 and 12 months. In a total of 131 graft failure cases, 18 mortalities, 42 infection-related hospitalizations, 22 cancer cases, 11 graft intolerance syndrome cases, and 28 re-transplantations occurred during the 94-month follow-up. Immunosuppressant maintenance significantly decreased the patient survival rate 6 months after graft failure compared with weaning (log-rank P = 0.008) and was an independent risk factor for mortality, even after adjustments (hazard ratio, 3.01; P = 0.025). Infection-related hospitalization, graft intolerance syndrome development, and re-transplantation were not affected by the immunosuppressant weaning protocol. Among the immunosuppressant weaning group, low-dose steroid maintenance at 6 and 12 months helped preserved RRF (P = 0.008 and P = 0.003, respectively).

Comparison between prasugrel and clopidogrel used as antiplatelet medication for endovascular treatment of unruptured intracranial aneurysms. A meta-analysis

Background Clopidogrel is routinely used to decrease ischemic complications during neurointerventional procedures. However, the efficacy may be limited by the antiplatelet resistance. Purpose To analyze the efficacy of prasugrel (PS) compared to clopidogrel (CP) in the cerebrovascular field. Data sources A systematic search of two large databases was performed for studies published from 2000 to 2018. Study selection According to PRISMA guidelines, we included studies reporting treatment-related outcomes of patients undergoing neurointerventional procedures under PS, and studies comparing PS and CP. Data analysis Random-effects meta-analysis was used to pool the following: overall rate of complications, ischemic and hemorrhagic events, influence of the dose of PS. Data synthesis Including 7 studies, 682 and 672 unruptured intracranial aneurysms were treated under PS (cases) and CP (controls), respectively. Low-dose (20 mg/5 mg) (loading and maintenance doses) of PS compared with the standard dose of CP (300 mg/75 mg) showed a significant reduction of the complication rate (OR = 0.36, 95% CI = 0.17–74, P = 0.006, I2 = 0%). Overall, ischemic complication rate was significantly higher among the CP group (40/672 = 6%, 95% CI = 3%–13%, I2 = 83% vs 16/682 = 2%, 95% CI = 1%–5%, I2 = 73%, P = 0.03). Low and high loading doses of PS were associated with 0.6% (5/535, 95% CI = 0.1%–1.6%, I2 = 0%) and 9.3% (13/147, 95% CI = 0.2%–18%, I2 = 60%) of intra-periprocedural hemorrhages, respectively (P = 0.001), whereas low and high maintenance doses of PS were associated with 0% (0/433) and 0.9% (2/249, 95% CI = 0.3%–2%, I2 = 0%) of delayed hemorrhagic events, respectively (P = 0.001). Limitations Retrospective series and heterogeneous endovascular treatments. Conclusions In our study, low-dose of prasugrel, compared with clopidogrel premedication, is associated with an effective reduction of the ischemic events with an acceptable rate of hemorrhagic complications.

Role of Post-Allogeneic Hematopoietic Stem Cell Transplantation Low-Dose Azacitidine for Prevention of Relapse in Patients with Acute Myeloid Leukemia and Myelodysplastic Syndrome: A Retrospective Analysis

Introduction Relapse after allogeneic hematopoietic stem cell transplantation (HSCT) for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) remains a major cause of treatment failure with associated poor prognosis. Low-dose post-HSCT maintenance azacitidine (AZA) has proved to be beneficial in preventing relapses (de Lima et al. Cancer 2010). Herein, we retrospectively evaluated outcomes of patients (pts) treated with low-dose AZA post-HSCT. Methods Pts with AML and MDS who underwent allogeneic HSCT between 2012-2018 at two centers were evaluated and categorized into AZA group (with low-dose AZA maintenance) and control group (without AZA maintenance). In control group, pts who died or relapsed prior to day +100, had grade III-IV aGVHD or received maintenance therapy other than AZA (e.g. FLT3 inhibitors) were excluded. Using Kaplan-Meier method, event (defined as relapse or death) free survival (EFS) and overall survival (OS) were computed and compared using log-rank test. Results A total of 107 patients were included; 53 (49.5%) in AZA and 54 (50.5%) in control groups. Disease and transplant-related characteristics are shown in table 1. Both groups were comparable with respect to age, diagnosis, disease risk stratification, disease status at HSCT, and MRD status at day +30 and day +100 (table 1). More pts received reduced intensity conditioning (RIC) in the AZA group (71.6% vs 37%, p= Conclusions In our cohort, low-dose AZA maintenance was generally well tolerated. The results of this study indicate that AZA maintenance is feasible and associated with improved EFS and OS. In addition, AZA has the potential of improving relapse rates even in pts who are unable to receive myeloablative conditioning as a significant number of pts in AZA group in this study received RIC. The optimal timing, duration of treatment and selection of pts most suitable for AZA for maximum benefit, however, requires further studies.

Maintenance 5-Azactidine May Improve Outcomes after Allogeneic Stem-Cell Transplantation in High-Risk AML and MDS Patients

<h3>Introduction</h3> Allogeneic stem-cell transplantation (SCT) is curative therapy in patients with AML or MDS. However, disease recurrence is the major cause of treatment failure. We explored the use of low-dose azacytidine maintenance therapy for the prevention of relapse after SCT in patients with high-risk AML/MDS. <h3>Methods</h3> Patients considered to be at high risk for relapse after SCT were given azacytidine at 32-50 mg/m2 for 5 days every 28 days for a planned duration of 2 years. Sct outcomes were compared with a historical group matched for age, disease, status at SCT, cytogenetics, conditioning and donor type and time from SCT to the start of maintenance. Patients relapsing after SCT and achieving second CR with chemotherapy were also eligible for secondary azacytidine prophylaxis. <h3>Results</h3> Forty patients with AML (n=32) or MDS (n=8), median age 62 years (25-74), were given azacytidine after SCT from sibling (n=8) or matched-unrelated (n=32) donors. The conditioning regimen was myeloablative (n=20) or reduced-intensity (n=20). The status at SCT was untreated MDS (n=10), CR1 (n=19), CR2 (n=4), refractory AML (n=7). 15 had normal karyotype, 9 complex karyotype and 16 other cytogenetic abnormalities (12 of them high-risk). Fifteen patients were in CR after SCT but at high-risk for relapse due to active disease (n=7) or positive measurable residual disease (MRD, n=3) at SCT, or poor-risk cytogenetics (n=5). 17 patients were given azacytidine pre-emptively for mixed-chimerism (n=9) or positive MRD (n=8) after SCT. 8 patients were given azacytidine as secondary prevention after achieving CR with chemotherapy for post-transplant relapse. The estimated leukemia-free survival (LFS) in this group of patients is less than 20%. Patients started azacytidine in a median of 2.2 months (1.2-6.9) after SCT and received a median of 14 courses (1-50). 3 patients were also given donor-lymphocyte infusions concomitantly. 12 of 23 patients given prophylactic azacytidine remained in CR, 11 relapsed and 7 of them died. 15 of 17 patients given azacytidine preemptively achieved a response (10 CR) and 7 remained in CR, 9 died of disease progression and one of non-relapse cause. With a median follow-up of 22.5 months (10.2-45.2), the estimated 3-year overall survival (OS) and LFS rates are 53.9% (95%CI, 29.5-78.4) and 40.0% (95%CI, 21.2-58.6), respectively. In the matched control group, 8 patients are alive, 26 died of relapse and 6 of non-relapse causes. The estimated 3-year OS and LFS rates are 27.1% (95%CI, 13.2-41.0, P=0.002, Figure 1) and 19.7% (95%CI, 7.9-32.1, P=0.005, Figure 2), respectively. <h3>Conclusions</h3> Maintenance azacytidine is safe and effective therapy when used prophylactically or preemptively after SCT in high-risk AML/MDS patients and may improve survival. Azacytidine maintenance should be further explored, possibly in combination with other methods to prevent relapse.

Single Center Real Life Experiences in the Treatment of Pediatric, Adolescent and Young Adult ALL Patients Using Commercially Available CAR-T-Cells in Germany – Susceptibility to Bridging Chemotherapy Predicts Response.

Background Although children, adolescents and young adult patients with ALL have in general a good prognosis relapses occur and patients with a second relapse, a relapse after allogeneic SCT or patients with primary refractory disease have a poor prognosis. In this patient group several studies using second generation CD19 chimeric antigen receptor T- cells (CAR-T cells) demonstrated high efficacy with survival rates of up to 65%. Here we report our first results using commercially available CAR-T-cell product Tisagenlecleucel in patients with ALL. Methods, Patients Between May 2016 and August 2019 twenty-six patients received a peripheral blood apheresis for CAR-T cell generation. Twenty-four patients had relapsed after allogeneic HSCT (92%), one patient suffered from second r/relapse (4%) or from primary r/ALL (4%). In 23/26 (88%) patients CAR-T cell production was possible after first apheresis, in 2 patients (4%) a second apheresis was necessary after failure of the first transduction. Patients' median age was 13.5 years (range: 1.1-33.2 years). Between apheresis and start of lymphodepleting chemotherapy (LDC) 24 patients received low dose maintenance chemotherapy according to the FRAPOSTALL protocol (Willasch et al. 2016) and two patients were treated with inotuzumab. Disease status at start of LDC was CR w/o MRD (n=12), and persistence of blasts (n=11). Results CAR-T cells could be transfused to 23/26 patients at a median dose of 1.5 Mio/kgBW (range 0.145 to 8.5) /kgBW. In two patients (8%) CAR-T cell production was not possible and in one patient, in whom a second viral transduction procedure was necessary, CAR-T cell transfusion could not be performed because of diseases progression and deterioration of the patients' general condition. Cytokine release syndrome (CRS) grade I-IV was observed in seven patients (30%); 14/23 patients (70%) did not develop CRS. Cytokine related encephalopathy syndrome (CRES) grade II was observed in 4/23 patients (17%). At day +28 17/23 patients (74%) achieved MRD negative CR. Three patients (13%) did not respond and three patients died before day +28. Thereof two patients (8%) with progressive disease at time of LDC who did not respond, and unfortunately one patient (4%) died in CR based on infection before day +28. As of 8/20/2019 median follow-up was 9.5 months. Patients with Conclusion These results confirm that commercial available CAR-T cell product Tisagenlecleucel (Kymriah®) showed high efficacy in ALL patients. Response to bridging chemotherapy and level of residual diseases prior to CAR-T infusion might impact the pEFS and survival of the patients.

Higher Omega-3 Index Is Associated with Better Asthma Control and Lower Medication Dose: A Cross-Sectional Study

Asthma is a chronic inflammatory airway disease, associated with systemic inflammation. Omega-3 polyunsaturated fatty acids (n-3 PUFA) have established anti-inflammatory effects, thus having potential as an adjunct therapy in asthma. This study aimed to compare erythrocyte n-3 PUFA in adults with (n = 255) and without (n = 137) asthma and determine the relationship between erythrocyte n-3 PUFA and clinical asthma outcomes. Subjects had blood collected, lung function measured and Juniper Asthma Control Questionnaire (ACQ) score calculated. Fatty acids were measured in erythrocyte membranes by gas chromatography, and the omega-3 index (O3I) was calculated (% eicosapentaenoic acid + % docosahexaenoic acid). O3I was similar in subjects with and without asthma (p = 0.089). A higher O3I was observed in subjects with controlled or partially controlled asthma (ACQ < 1.5) compared to subjects with uncontrolled asthma (ACQ ≥ 1.5) (6.0% (5.4–7.2) versus 5.6% (4.6–6.4) p = 0.033). Subjects with a high O3I (≥8%) had a lower maintenance dose of inhaled corticosteroids (ICS) compared to those with a low O3I (<8%) (1000 μg (400–1000) versus 1000 μg (500–2000) p = 0.019). This study demonstrates that a higher O3I is associated with better asthma control and with lower ICS dose, suggesting that a higher erythrocyte n-3 PUFA level may have a role in asthma management.

Negative symptoms predict high relapse rates and both predict less favorable functional outcome in first episode psychosis, independent of treatment strategy

BackgroundIn first episode psychosis (FEP) baseline negative symptoms (BNS) and relapse both predict less favorable functional outcome. Relapse-prevention is one of the most important goals of treatment. Apart from discontinuation of antipsychotics, natural causes of relapse are unexplained. We hypothesized that BNS, apart from predicting worse functional outcome, might also increase relapse risk. MethodsWe performed a post-hoc analysis of 7-year follow-up data of a FEP cohort (n = 103) involved in a dose-reduction/discontinuation (DR) vs. maintenance treatment (MT) trial. We examined: 1) what predicted relapse, 2) what predicted functional outcome, and 3) if BNS predicted relapse, whether MT reduced relapse rates compared to DR. After remission patients were randomly assigned to DR or MT for 18 months. Thereafter, treatment was uncontrolled. OutcomesBNS and duration of untreated psychosis (DUP) predicted relapse. Number of relapses, BNS, and treatment strategy predicted functional outcome. BNS was the strongest predictor of relapse, while number of relapses was the strongest predictor of functional outcome above BNS and treatment strategy. Overall and within MT, but not within DR, more severe BNS predicted significantly higher relapse rates. Treatment strategies did not make a difference in relapse rates, regardless of BNS severity. InterpretationBNS not only predicted worse functional outcome, but also relapses during follow-up. Since current low dose maintenance treatment strategies did not prevent relapse proneness in patients with more severe BNS, resources should be deployed to find optimal treatment strategies for this particular group of patients.

Sustained successful peanut oral immunotherapy associated with low basophil activation and peanut-specific IgE

Oral immunotherapy (OIT) can successfully desensitize many peanut-allergic subjects, but clinical tolerance diminishes over time on discontinuation, or low-dose maintenance, of peanut. Therefore, to improve the efficacy and sustainability of such therapy, we sought to identify biomarkers and clinical tools that can predict therapeutic outcomes and monitor treatment responses. We evaluated whether basophil activation in whole blood, and plasma levels of peanut-specific immunoglobulins, are useful biomarkers for peanut OIT. We longitudinally measured, before, during, and after OIT, basophil activation in whole blood exvivo in response to peanut stimulation, and peanut-specific IgE (sIgE) and peanut-specific IgG4 (sIgG4), in a large, single-site, double-blind, randomized, placebo-controlled, phase 2 peanut OIT study. We compared basophil responsiveness and peanut-specific immunoglobulins between those who were clinically reactive and those who were tolerant to peanut oral challenges. Peanut OIT significantly decreased basophil activation, peanut sIgE, Ara h 1, Ara h 2, and Ara h 3 IgE levels, and sIgE/total IgE, but increased sIgG4/sIgE. Participants who became reactive to 4 g of peanut 13 weeks off active OIT exhibited higher peanut-induced basophil activation exvivo and higher peanut sIgE levels and sIgE/total IgE, but lower sIgG4/sIgE. Notably, participants entering the study with low basophil responsiveness were more likely to achieve treatment success. Substantial suppression of basophil activation was required to maintain long-term clinical tolerance after peanut OIT. Assessments of peanut-induced basophil activation and peanut-specific immunoglobulins can help to predict treatment outcomes, and to differentiate transient desensitization versus sustained unresponsiveness after OIT.

Long-term Treatment With Proton Pump Inhibitor Is Effective in Children With Eosinophilic Esophagitis

To evaluate the long-term efficacy and safety of proton pump inhibitors (PPIs) in pediatric eosinophilic esophagitis (EoE).One hundred and nine children between 1 month and 15 years of age with esophageal symptoms and EoE were recruited at 2 pediatric hospitals in Madrid between February 2013 and August 2017. All patients were treated with esomeprazole for 8 weeks, and 72 (66%) achieved histologic remission. Of the 72, 57 children were enrolled in this 1-year study.This was a prospective study of 57 children (73.7% boys, median age 11 years) with EoE who reached complete or partial histologic remission after an 8-week esomeprazole trial (1 mg/kg per dose, twice daily). Esomeprazole was continued at 1 mg/kg per day (max 40 mg daily) for 1 year. Patients were closely monitored every 3 months for symptom recurrence, clinical outcomes, and adverse events. Follow-up endoscopy was performed at 1 year or before, if symptoms recurred. Complete histologic remission was defined as ≤5 eosinophils per high-power field, and partial remission was defined as >5 and <15 eosinophils per high-power field. Patients were not treated with concomitant dietary restrictions or topical steroids.After 12 months of PPI maintenance therapy, histologic remission continued in 70.1% (n = 40) of children. Long-term remission was observed more frequently in children with initial complete histologic remission compared with those with partial remission (81% vs 50%, P = .014). There were no other clinical, endoscopic, or histologic data to predict remission on PPI therapy. Eleven of 12 children (91.6%) who remained on esomeprazole at a lower maintenance dose (0.5 mg/kg per day) for an additional 12 months also sustained histologic remission. Five children developed adverse events on esomeprazole (0.7–2 mg/kg per day), including diarrhea, urticaria, and headache. All adverse events self-resolved or improved by substituting for another PPI.Long-term PPI therapy is safe and effective for the treatment of pediatric EoE. At 1 year follow-up, 70% of children with PPI-responsive EoE remained in histologic and clinical remission on a low-dose maintenance regimen. Patients with complete histologic remission after an 8-week trial of PPI were more likely to maintain histologic remission with maintenance PPI.This is a landmark prospective study supporting the use of PPI therapy for the long-term treatment of EoE in a subset of pediatric patients. Seventy percent efficacy after 12 months of PPI is comparable or higher than reported remission rates for alternative EoE therapies, such as dietary restriction or swallowed corticosteroids. Future studies will need to compare therapies and determine if PPI dose escalation can lead to improved remission rates.

Maintenance 5-Azactidine May Improve Outcomes after Allogeneic Stem-Cell Transplantation in High-Risk AML and MDS Patients

Introduction: Allogeneic stem-cell transplantation (SCT) is curative therapy in patients with AML or MDS. However, disease recurrence is the major cause of treatment failure. 5-Azacytidine has been used in the standard treatment of MDS and also in the treatment of AML patients not eligible for standard chemotherapy. There is limited data on the safety and efficacy of Azacytidine after SCT. We explored the use of low-dose Azacytidine maintenance therapy for the prevention of relapse of AML/MDS after SCT. Methods: Patients considered to be at high risk for relapse after SCT were given Azacytidine at 32-50 mg/m2 for 5 days every 28 days for a planned duration of 2 years. Transplantation outcomes were compared with a historical group matched for patient age, disease, status at SCT, cytogenetics, conditioning and donor type. To reduce bias, control patients were required to be alive and in remission for at least the time until the start of Azacytidine prophylaxis in their counterparts. Patients relapsing after SCT and achieving second CR with chemotherapy were also eligible for secondary Azacytidine prophylaxis. The control patients for these patients were also matched for the time from SCT to relapse. Results: Forty patients, median age 62 years (25-74), 24 male and 16 female, were given azacytidine after SCT from HLA-matched sibling (n=8) or matched-unrelated (n=32) donors. Diagnosis was AML (n=32) or MDS (n=8). The conditioning regimen was myeloablative (n=20) or reduced-intensity (n=20). The status at SCT was untreated MDS/ secondary AML (n=10), CR1 (n=19), CR2 (n=4), refractory AML (n=7). 15 had normal karyotype, 9 complex karyotype and 16 other cytogenetic abnormalities (12 of them high-risk). Fifteen patients were in CR after SCT but at high-risk for relapse due to active disease (n=7) or positive MRD (n=3) at SCT, or poor-risk cytogenetics (n=5). Eight patients were given Azacytidine as secondary prevention after achieving CR with chemotherapy for post-transplant relapse. 17 patients were given Azacytidine pre-emptively for mixed-chimerism (n=9) or positive measurable residual disease (n=8) after SCT. The estimated leukemia-free survival (LFS) in this group of patients is less than 20%. Patients started Azacytidine in a median of 2.2 months (1.2-6.9) after SCT and received a median of 14 courses (1-50). Three patients were also given donor-lymphocyte infusions concomitantly with Azacytidine. 18 patients are still on therapy, 16 died or progressed, 3 stopped after long remission, 2 stopped due to regulatory issues and only 1 had to discontinue due to toxicity. 12 of 23 patients given prophylactic Azacytidine remained in CR, 11 relapsed and 7 of them died. 15 of 17 patients given Azacytidine preemptively achieved a response (10 CR) and 7 remained in CR. 9 died of disease progression and one of non-relapse cause. With a median follow-up of 22.5 months (10.2-45.2), the estimated 3-year overall survival (OS) and LFS rates are 53.9% (95%CI, 29.5-78.4) and 40.0% (95%CI, 21.2-58.6), respectively. In the matched control group, 8 patients are alive, 26 died of relapse and 6 of non-relapse causes. The estimated 3-year OS and LFS rates are 27.1% (95%CI, 13.2-41.0, P=0.002, Figure 1) and 19.7% (95%CI, 7.9-32.1, P=0.005, Figure 2), respectively. The relapse rates were 57.6% (95%CI, 41.6-79.8) and 65.3% (95%CI, 52.0-82.0) in the Azacytidine and control groups, respectively (P=0.04, Figure 3). The median time to relapse was 9.1 months (0.7-25.5) and 4.9 months (1.1-35.9), respectively. The non-relapse mortality (NRM) rates were 2.5% (95%CI, 0.3-17.3) and 15.0 (7.1-31.4), respectively (P=0.01). Conclusions: Azacytidine is safe and effective therapy when used prophylactically or preemptively in high-risk AML/MDS patients to prevent relapse. Azacytidine maintenance may reduce but more often delay relapse in this high-risk patient group. Azacytidine may also reduce NRM and improve survival in this patient group and should be further explored, possibly in combination with other methods to prevent relapse. Figure 1 Disclosures No relevant conflicts of interest to declare.

Outcomes of Lenalidomide Retreatment with Novel Triplet Regimens in Multiple Myeloma Patients Progressing on Lenalidomide-Based Maintenance Therapy: A Single Center Retrospective Analysis

Outcomes of Lenalidomide Retreatment with Novel Triplet Regimens in Multiple Myeloma Patients Progressing on Lenalidomide-Based Maintenance Therapy: A Single Center Retrospective Analysis

486P - Phase II study of low-dose afatinib maintenance treatment for patients with EGFR-mutated non-small cell lung cancer (NJLCG1601)

BackgroundAfatinib is a 2nd generation EGFR-TKI and has been a standard first line treatment for patients (pts) with advanced NSCLC with EGFR mutations. Afatinib has good efficiency, whereas afatinib has severe adverse events (AEs) and often lead to discontinuation of treatment or a dose reduction. NJLCG1601 was conducted to evaluate the efficacy of low-dose afatinib maintenance treatment. MethodsEGFR-TKI-naïve stage III / IV / recurrent NSCLC pts harboring EGFR mutations (exon 19 deletion or exon 21 L858R or minor mutation) were enrolled. Pts received afatinib 40mg orally once a day. When prescribed AEs (grade ≧ 2 in CACAE ver 4.0) or unacceptable AEs occurred, a dose of afatinib was reduced from 40mg to 30mg, 30mg to 20mg. The treatment was continued until disease progression, occurrence of intolerable severe AEs, or withdrawal of consent. The primary endpoint was 1-year progression free survival (PFS) rate. Secondary endpoints were PFS, overall response rate (ORR), the incidence of AEs, and the incidence of grade ≧ 3 AEs. Assuming a threshold 1-year PFS rate of 42% and an expected 1-year PFS rate of 63%, a total of 26 pts was required to have 90% power at a two-tailed alpha of 0.05. This is a subset analysis of patients with adenocarcinoma in NJLCG1601 study (Trial Identifier, UMIN000020688). ResultsBetween Apr 2016 and Sep 2017, 30 pts were enrolled. Among 30 patients, 28 patients (93%) were adenocarcinoma. Pts characteristics were as follows: median ages, 70 years (range 46-79 years); proportion of males, 43%; clinical stage, IV 61% and post-op 39%; EGFR mutation types, exon 19 deletion 54%, ex21 L858R 36%, and minor mutations 11%. 1-year PFS rate was 53.6% (95% CI, 33.8-69.8), median PFS was 13.0 months, and ORR was 78.6%. Dose reductions occurred in 86% (24/28). Incidence of all cause grade ≧ 3 was 60% which is smaller than the frequency of Japanese subset in LUX-Lung 3. ILD was occurred in 3 patients and 1 patients died. Treatment-related deaths were observed in 2 pts. ConclusionsLow-dose afatinib maintenance treatment reduced treatment-related adverse events without detracting from the therapeutic efficacy. Legal entity responsible for the studyUMIN000020688. FundingHas not received any funding. DisclosureA. Nakamura: Honoraria (self): MSD; Honoraria (self): Chugai; Honoraria (self): AstraZeneca. S. Inoue: Honoraria (self): AstraZeneca; Honoraria (self): Eli Lilly; Honoraria (self): MSD; Honoraria (self): Otsuka Pharmaceutical; Honoraria (self), research funding: Kyorin Pharmaceutical; Honoraria (self): Ono Pharmaceutical; Honoraria (self): GlaxoSmithKline; Honoraria (self): Daiichi Sankyo Company; Honoraria (self): Taiho Pharmaceutical; Honoraria (self): Chugai Pharmaceutical; Honoraria (self): Teijin Pharma; Honoraria (self), research funding: Novartis Pharma; Honoraria (self): Pfizer Inc; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Meiji Seika Pharma. S. Sugawara: Honoraria (self): AstraZeneca; Honoraria (self): Chugai Pharma; Honoraria (self): Nippon Boehringer Ingelheim; Honoraria (self): Taiho Pharmaceutical; Honoraria (self): Pfizer; Honoraria (self): Eli Lilly; Honoraria (self): Novartis; Honoraria (self): Kyowa Hakko Kirin; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Ono Pharmaceutical; Honoraria (self): MSD. All other authors have declared no conflicts of interest.

1360. Disseminated Mycobacterium abscessus Infections in Patients with Neutralizing Anti-interferon-gamma Autoantibodies Treated with Rifabutin-based Combination Regimens

BackgroundThis prospective study aimed to describe the treatment and safety outcomes of rifabutin-based combinations which has been shown to be synergistic in vitro, for patients with refractory M. abscessus infections and neutralizing anti-IFNγ antibodies.MethodsPatients failing at least two standard macrolide-based regimens were recruited from hospitals across Taiwan since August 2017. They received rifabutin (RFB > 300 mg/day) initially with azithromycin (AZR 500 mg/day) and at least one parenteral agent and were monitored thereafter clinically on a monthly basis and by 3–6 monthly PET-CT imaging.ResultsOf 12 referred patients, only four had complete evaluations. The median age was 41 years and follow-up duration was 543 (range 307–668) days. All patients had lung and lymph node disease, two also had liver, bone and joint involvements and all were HLA-DR 16:02, HLA-DQ 05:02 positive. Prior to starting RFB–AZR, they had received at least four successive antimycobacterial regimens, but showed progression of existing lesions (2) or new lesions (2). Following RFB–AZR, all four patients experienced adverse reactions, including reactive dermatoses (2), fevers (2), leukopenia (2), thrombocytopenia (1), hearing loss (1), acute kidney injury (1), which necessitated withdrawal of rifabutin (4), short-term steroid use (2), and replacement of tenofovir with entecavir for chronic hepatitis B (1). All patients recovered fully from these adverse effects. Rifabutin was successfully restarted on first attempt (3) and on third attempt (1). The longest symptom-free interval on RFB–AZR was 331 days and the lowest maintenance dose was RFB 150–AZR 250 thrice weekly. Follow-up PET-CT confirmed good resolution of previous hot spots (mean SUVmax −4.5) except for the patient who did not tolerate RFB 300 due to fever and nausea on the first re-challenge, whose PET-CT detected a slight increase in mean SUVmax +0.6 and was hospitalized for dry cough on daily AZR–ciprofloxacin. The latter eventually tolerated a lower daily dose RFB 150–AZR 250 and became asymptomatic.ConclusionRifabutin is an oral agent that can be effectively combined with azithromycin in long-term maintenance regimens against M. abscessus in immunodeficient adults. Adverse effects are frequent early on; however, rechallenge appears to be safe and outcomes favorable. Disclosures All authors: No reported disclosures.

P3671Selexipag dosing and titration in the first 500 patients enrolled in SPHERE (SelexiPag: tHe UsErs dRug rEgistry)

Abstract Introduction SPHERE is an ongoing US-based, multicentre, prospective, registry collecting data on use of the oral selective IP prostacyclin receptor agonist selexipag in real-world settings. Here, we report selexipag dosing and titration in the first 500 patients. Methods SPHERE, initiated in November 2016, will enrol 800 patients newly initiated on or already treated with selexipag at enrolment who have a documented titration regimen. Patients are followed for up to 18 months. Patients were considered “newly initiated” on selexipag if they were enrolled in SPHERE ≤60 days after starting selexipag and were considered “previously initiated” if they enrolled &gt;60 days after starting selexipag. The highest dose is the maximum dose reached during up-titration within 6 months since initiation. Selexipag “maintenance dose” is defined as the first dose received for ≥14 days without interruption or change; “titration speed” is defined as the highest dose reached within the first 6 months after initiation divided by the time (in weeks) to reach it. Results The data cut-off for this analysis was December 20, 2018. Most patients had Group 1 pulmonary hypertension (PH) (95.4%), which was primarily idiopathic (49.6%) or connective tissue disease associated (26.0%). At selexipag initiation 49.8% of patients had functional class III symptoms. At the time of selexipag initiation, 19.2% of patients were on PH therapy containing a prostacyclin pathway agent (PPA) (8.5% with a parenteral PPA). The median maintenance dose of selexipag was 1200 μg BID (IQR: 800–1600 μg BID) and the median time to reach it was 8.1 wks (IQR: 5.3–11.0 wks). Low (≤400 μg BID), medium (600–1000 μg BID), and high (≥1200 μg BID) maintenance doses were attained by 15.1%, 30.8%, and 49.5% of patients, respectively (and in 23.2%, 31.2%, and 36.2%, respectively, in GRIPHON). The median titration speed was 175 μg BID/wk (IQR: 110.5–195.3 μg BID/wk), slower than the protocol-outlined 200 μg BID/wk in GRIPHON. In SPHERE, most patients titrated at speeds &lt;200 μg BID/wk, regardless of whether they were newly (175 μg BID/wk; IQR 118.6, 195.3) or previously (175 μg BID/wk; IQR 109.8, 195.3) initiated. As expected, more patients discontinued due to adverse events in the newly (29.0%) versus previously (14.1%) initiated groups. The most common adverse events leading to selexipag discontinuation were worsening pulmonary hypertension (2.2%), headache (2.0%), myalgia (1.4%), and nausea (1.0%). Conclusion The median maintenance selexipag dose in SPHERE was 1200 μg BID. While the median titration speed was 175 μg BID/wk, there was marked variation and the vast majority of patients titrated slower than 200 μg BID/wk. No new safety signals were observed. Acknowledgement/Funding Actelion Pharmaceuticals US, Inc.

1510P - Delayed onset immune related adverse effects (IRAEs) of pembrolizumab in non-small cell lung cancer

BackgroundThe humanised PD1 antibody, Pembrolizumab, is used as monotherapy in the 1st and 2nd line setting for patients with advanced non-small cell lung cancer (NSCLC). There is a lack of data about the delayed onset of IRAEs which is important as patients can be on prolonged treatment. MethodsThis is a retrospective study of NSCLC patients treated with pembrolizumab across 4 institutions in London (North Middlesex University Hospital, Princess Alexandra Hospital, St. Bartholomew’s Hospital and University College London Hospital). IRAEs recorded on clinic letters from start of treatment until March 2019 were categorised as early (<180 days from first dose) or delayed (>180 days). Results139 patients (60% male) with advanced NSCLC were treated with pembrolizumab. Median age was 67 years and 75% (104/139) were adenocarcinoma. Median follow up was 191 days with 3 patients completing 2 years of treatment. IRAEs were reported in 53% (73/139) with patients experiencing up to five different IRAEs. 34% (40/116) of all IRAEs were delayed and colitis was the most common (54%) late IRAE, followed by skin & mucosal toxicities (Table). There were no differences in the grade of severity (P=0.37) or number of toxicities requiring permanent discontinuation of pembrolizumab between early and delayed IRAEs (P=0.31). All patients with pneumonitis, 88% with hepatitis and 87% with colitis were treated with steroids. In 88% (35/40) of patients with delayed IRAEs, toxicities resolved or became asymptomatic. All but 2 cases of endocrinopathy required chronic hormone replacement therapy. 19 cases of treating through toxicity with maintenance low dose corticosteroid were identified. Of these, only one developed progressive disease with the remainder continuing to receive pembrolizumab.Table1510PTableIRAEsEarlyDelayedGeneral e.g. Fatigue172Rash/Pruritis2311Colitis1112Hypo/Hyperthyroidism73Hepatitis53Pneumonitis53Hypophysitis22Arthritis13Blepharitis/Conjunctivitis31Polymyalgia/Myositis21Nephritis01TOTAL76 (66%)40 (34%) ConclusionsDelayed onset IRAEs are common and exhibit a different profile of toxicities compared to early onset. They are no more severe than early IRAEs and can be effectively managed to allow patients to continue their treatment. Legal entity responsible for the studyNorth Middlesex University Hospital, Princess Alexandra Hospital, St. Bartholomew’s Hospital and University College London Hospital. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Dopamine agonists in prolactinomas: when to withdraw?

Dopamine agonists (DAs) are well recognized as the first-line therapy for prolactinomas due to their efficacy in achieving tumoral shrinkage and normoprolactinemia. However, it remains to be established the best timing to withdraw DAs and in which patients this should be attempted. Studies in the 1980s, mainly using bromocriptine, started to defy the concept that DAs should be regarded as a lifelong therapy considering that sustained normoprolactinemia was attained in a small subset of patients after drug withdrawal. The introduction of the more effective agent cabergoline led to an increase in the percentages of remission. The most recent meta-analysis on the topic stated than remission rates after withdrawal can range from 15% in macroprolactinoma patients treated with bromocriptine to 41% in those with microprolactinomas previously treated with cabergoline. When more stringent criteria were applied before attempting withdrawal, sustained remission ensued in more than 50% of the individuals. Treatment duration for more than 24months, the achievement of normoprolactinemia, marked reduction (≥ 50%) in tumoral size and DAs tapering till a low maintenance dose (e.g. cabergoline 0.5mg/week) have been the most consistently identified predictors of success. In addition, a growing amount of evidence suggests that the post-pregnancy/breastfeeding period and menopause are reasonable timings to re-access the need for continuing DAs therapy. Considering that the achievement of sustained normoprolactinemia is still far from being universal after the withdrawal, even in highly selected cohorts, future larger prospective studies should continue to address this issue.