Inhibitors In Children Research Articles

Insurance Delays in Initiation of Tumor Necrosis Factor Inhibitors in Children With Juvenile Idiopathic Arthritis

Insurance Delays in Initiation of Tumor Necrosis Factor Inhibitors in Children With Juvenile Idiopathic Arthritis

BAFF rs9514828 gene polymorphism and the risk of the development of inhibitors in children with severe haemophilia A.

Haemophilia A (HA) is an x-linked recessive disease due to deficiency of coagulation factor VIII (FVIII). The development of neutralizing antibodies (inhibitors) against infused FVIII is a major concern. B cell activating factor (BAFF) has been implicated in several autoimmune diseases. We aimed to evaluate the possible association of BAFF rs9514828 gene polymorphism and the risk of the development of FVIII inhibitor in children with severe HA. This cohort study was carried out on 100 newly diagnosed boys with severe HA who were never treated before with FVIII concentrate. Assessment of serum levels of BAFF and BAFF rs9514828 genotyping at first diagnosis was performed and the patients were followed up for the completion of a total of 50 exposure days or the development of inhibitors whichever occurred first. The patients were divided as positive or negative according to the presence or absence of inhibitors. The risk allele for BAFF rs9514828 (T) was significantly more frequent in the inhibitor positive patients than the inhibitor negative patients (P=.003). In addition, CT+TT genotypes were associated with increased risk of FVIII inhibitor development. Receiver operating characteristics (ROC) analysis showed that BAFF levels could predict the development of FVIII inhibitors at a cut-off value of ≥ .92 with a sensitivity of 85.9% and a specificity of 80.2%. BAFF rs9514828 gene polymorphism could be independent risk factor and elevated BAFF levels might be useful prognostic marker for the development of FVIII inhibitor in newly diagnosed children with severe HA.

Proton pump inhibitors are still overprescribed for hospitalized children

ObjectiveThe use of proton pump inhibitors has increased exponentially over the past 20 years. Several side effects have been reported and concerns exist about the consequences of long-term proton pump inhibitors on health, leading to limitation of their use. The present study analyzed prescriptions of proton pump inhibitors at inpatient units and assessed their compliance with current recommendations. MethodsThis single-center, observational, retrospective study reviewed medical file of patients hospitalized at the pediatric medical departments of the Bordeaux University Hospital between April 1 and September 30, 2019. Patients younger than 18 years, hospitalized in the pediatric hospital units and treated with proton pump inhibitors were included. Prescriptions of proton pump inhibitors were compared with French and international guidelines. ResultsProton pump inhibitors were prescribed for 251 of 2237 children (11%), mainly for gastroesophageal reflux disease (47%) and prevention of peptic ulcer disease (32.7%). Proton pump inhibitor prescription complied to recommendations in 34.5% of cases, less often in children aged younger than 1 year (13.5%) than in older children. Compliance to recommendations was lower when proton pump inhibitors were indicated for the prevention of peptic disease (5%) than for gastroesophageal reflux disease (48%). ConclusionsProton pump inhibitors are frequently prescribed for hospitalized children, and indications comply with recommendations in only 35% of the cases. Efforts in spreading awareness of the recommendations on the use of proton pump inhibitors in children are mandatory among hospital pediatricians.

Safety and Efficacy of Immune Checkpoint Inhibitors in Children and Young Adults with Haematological Malignancies: Review and Future Perspectives.

Despite the marked improvement in overall survival rates of paediatric patients with haematological malignancies that has been achieved during the last decades, there is still a pressing need for novel therapeutic approaches for the subset of patients with relapsed or refractory disease. Immune checkpoint inhibitors aim to induce potent anti-tumour immune responses by targeted blocking of inhibitory receptors and have shown promising results in preclinical models and studies on the adult population. However, paediatric malignancies present unique features, and so far, experience with these agents is limited. In the current review, we present an overview of efficacy and safety data from case reports, case series, and clinical trials employing the use of immune checkpoint inhibitors in children, adolescents, and young adults with haematological malignancies. We also discuss new possibilities involving novel targets and combination treatments and provide a summary of the currently registered clinical trials.

A Narrative Review on Efficacy and Safety of Proton Pump Inhibitors in Children.

Proton pump inhibitors (PPIs) are among the most prescribed drugs worldwide and include omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole. Their use in pediatrics is approved for children older than 1 year, for the short-term treatment of symptomatic gastroesophageal reflux disease (GERD), healing of erosive esophagitis, treatment of peptic ulcer disease, and eradication of Helicobacter pylori. PPIs are also considered the standard of care for pediatric eosinophilic esophagitis. Despite the strict range of indications, the use of this class of molecules has increased in all pediatric age ranges. The long-term gastric acid suppression in children has been linked to increased risks of gastrointestinal and lower respiratory tract infections, bone fractures, and allergy. This study aims to provide a comprehensive overview of the mechanism of actions, use (and misuse) in infants and children, and safety of PPIs.

Persistence of Chronic Inflammation Despite Years of Transfusion Program in SCD Patients: Changing Red Blood Cells Is Not Sufficient to Treat Sickle Cell Disease

▪Sickle cell disease (SCD) is a severe hemoglobinopathy due to abnormal hemoglobin S (HbS). Although red blood cell dysfunction is at the core of the SCD pathophysiology, several studies have highlighted the important role of inflammatory cells like neutrophils. One of the most serious complications of SCD is cerebral vasculopathy (CV), due to the occlusion of one or more intracranial or cervical arteries. In 1998, the STOP study demonstrated that monthly blood transfusions could reduce the risk of stroke by 90% in children with CV. However, there is large heterogeneity in the evolution of CV under chronic transfusion, sometimes requiring exchange transfusion (ET) program for years without succeeding in healing the CV.The aim of the study is to investigate the impact of long-term transfusion program on neutrophil dysfunction, in order to understand if persistent inflammation could contribute to the non-healing of CV despite HbS permanently below 40%. In SCD children undergoing ET program for at least 1 year, we analysed i)the phenotype of neutrophils with 8 markers of activation/adhesion/ageing, ii)the plasmatic levels of elastase, witnessing the NETose activity of neutrophils, and iii)the ex-vivo adhesion of neutrophils on activated endothelial cells.One hundred and two SCD children with an ET transfusion program for at least 6 months because of CV were included in the study. ET session, carried out every 5 weeks and most of the time by erythrapheresis, reached their biological objectives with a mean HbS rate after ET session of 14.1%, and 35.4% before the next ET session, which means that these patients globally live at an average HbS level of 24% for at least 1 year. We managed to limit iron overload with a mean ferritinemia of 207 µg/L in the whole cohort. Despite these satisfactory results in terms of HbS reduction, the efficiency in curing the CV was modest in accordance with the previously described efficiency of ET program in SCD children: after a mean ET program duration of 4.4 years only 22% of them had an improvement of their CV since the beginning of the ET program, while 60% of them had a stagnation of their CV, and 18% of them worsened their vascular lesions. Considering inflammatory parameters, the patients had persistence of high leukocytosis and high neutrophils count (respective mean of 9810 G/L and 5742 G/L), significantly not different of neutrophils count before inclusion in the ET program. In a random subgroup of 20 patients, we analysed neutrophils phenotype, NETose and endothelial adhesion and compared them to healthy controls and SCD children without ET, treated or not with Hydroxyurea (HU). Overall, we observed as expected an activated, aged and adherent profile of neutrophils from untreated SCD children compared to healthy controls, characterized by an overexpression of CD18/CD11b (p=0,03), CD18/CD11a (p=0,02), CD162 (p=0,01), CD66a (p=0,01) and the ageing markers CD184 high/CD62Llow (p=0,04) as well as a higher plasmatic level of elastase (p=0. 01) and higher adhesion of neutrophils to endothelial cells. All these parameters were alleviated in SCD patients treated with HU. In SCD patient undergoing ET program, we found a similar profile of activated neutrophils to that of untreated SCD patients with a similar expression of activation molecules, high level of elastase and the same increase of neutrophils adhesion to endothelial cells compared to controls, witnessing a persistence of chronic inflammation despites years of ET.Overall, our study highlights that the replacement of sickle red blood cells, even for years, is not sufficient to reverse the deleterious inflammatory phenotype of neutrophils. Given the major role of inflammation in endothelial dysfunction, these could contribute to the persistence of CV in a majority of patients despite efficient ET programs. This raises the question of systematically combining ET program with anti-inflammatory treatment such as HU or P-selectin inhibitors in children with CV. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Renoprotection with sodium-glucose cotransporter-2 inhibitors in children: Knowns and unknowns.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors represent novel hypoglycemic drugs for the treatment of adult diabetes that have shown considerable potential for cardioprotection and renoprotection. This new drug can inhibit SGLT2 at the proximal tubule, increase glucosuria and natriuresis, and thus decreases the serum glucose level and blood pressure. Furthermore, the tubuloglomerular feedback activated by the natriuresis can decrease glomerular hyperfiltration, acknowledged as the main foundation of renoprotection. Several studies have confirmed the protective effects of SGLT2 inhibitors on the kidneys of adult diabetic patients and those with non-diabetic nephropathy; however, limited researches are seen in paediatric patients. In this review, we have summarized the mechanisms of action of SGLT2 inhibitors, the current experiences in adults, results of exploratory studies in children, and adverse events & obstacles of paediatric use. We further explore the potential and possible future research direction of SGLT2 inhibitors in paediatric diseases.

When it comes to drug access, should children be considered small adults? Countering coverage denials of FLT3 inhibitors in children with FLT3-ITD AML.

Pediatric Blood & CancerVolume 68, Issue 11 e29278 COMMENTARY When it comes to drug access, should children be considered small adults? Countering coverage denials of FLT3 inhibitors in children with FLT3-ITD AML Tristan E. Knight, Corresponding Author Tristan E. Knight knight.tristan@gmail.com orcid.org/0000-0002-7828-1522 Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children (SickKids) and the University of Toronto, Toronto, Ontario, Canada Correspondence Tristan Knight, The Hospital for Sick Children (SickKids), Pediatric Hematology & Oncology, 555 University Ave, Toronto, ON, Canada M5G 1X8. Email: knight.tristan@gmail.comSearch for more papers by this authorYubin Ge, Yubin Ge Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan, USA Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, USASearch for more papers by this authorJeffrey W. Taub, Jeffrey W. Taub orcid.org/0000-0003-2228-3235 Division of Hematology/Oncology, Children's Hospital of Michigan, Detroit, Michigan, USA Department of Pediatrics, Wayne State University School of Medicine, Detroit, Michigan, USA Department of Pediatrics, Central Michigan University, Mt. Pleasant, Michigan, USASearch for more papers by this authorJohann Hitzler, Johann Hitzler orcid.org/0000-0003-1158-186X Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children (SickKids) and the University of Toronto, Toronto, Ontario, Canada Developmental and Stem Cell Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario, CanadaSearch for more papers by this authorJoerg Krueger, Joerg Krueger Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children (SickKids) and the University of Toronto, Toronto, Ontario, CanadaSearch for more papers by this author Tristan E. Knight, Corresponding Author Tristan E. Knight knight.tristan@gmail.com orcid.org/0000-0002-7828-1522 Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children (SickKids) and the University of Toronto, Toronto, Ontario, Canada Correspondence Tristan Knight, The Hospital for Sick Children (SickKids), Pediatric Hematology & Oncology, 555 University Ave, Toronto, ON, Canada M5G 1X8. Email: knight.tristan@gmail.comSearch for more papers by this authorYubin Ge, Yubin Ge Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan, USA Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, USASearch for more papers by this authorJeffrey W. Taub, Jeffrey W. Taub orcid.org/0000-0003-2228-3235 Division of Hematology/Oncology, Children's Hospital of Michigan, Detroit, Michigan, USA Department of Pediatrics, Wayne State University School of Medicine, Detroit, Michigan, USA Department of Pediatrics, Central Michigan University, Mt. Pleasant, Michigan, USASearch for more papers by this authorJohann Hitzler, Johann Hitzler orcid.org/0000-0003-1158-186X Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children (SickKids) and the University of Toronto, Toronto, Ontario, Canada Developmental and Stem Cell Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario, CanadaSearch for more papers by this authorJoerg Krueger, Joerg Krueger Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children (SickKids) and the University of Toronto, Toronto, Ontario, CanadaSearch for more papers by this author First published: 06 August 2021 https://doi.org/10.1002/pbc.29278Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Volume68, Issue11November 2021e29278 RelatedInformation

Low‐dose immune tolerance induction alone or with immunosuppressants according to prognostic risk factors in Chinese children with hemophilia A inhibitors

BackgroundIn developing countries, children with hemophilia A (HA) with high‐titer inhibitor and poor immune tolerance induction (ITI) prognostic risk(s) cannot afford the recommended high‐ or intermediate‐dose ITI. ObjectivesTo determine the efficacy of low‐dose ITI (plasma‐derived factor VIII [FVIII]/von Willebrand factor at 50 FVIII IU/kg every other day) by itself (ITI‐alone) or combined with immunosuppressants rituximab and prednisone (ITI‐IS) in children with HA with high‐titer inhibitor. MethodsAll enrolled patients had pre‐ITI inhibitor ≥10 BU. We used ITI‐alone if inhibitor titer was <40 BU pre‐ITI and during ITI, and ITI‐IS if titer was ≥100 BU (historic) or ≥40 BU (pre‐ or during ITI) or if the patient was nonresponsive on ITI‐alone. ResultsFifty‐six children were analyzable, with median historic peak inhibitor titer 48.0 BU and followed for median 31.4 months. Overall, 35 (62.5%) achieved phase 2 success with negative inhibitor and normal FVIII recovery. The phase 2 success rate was 95% for the 20 patients receiving ITI‐alone. For the 36 patients receiving ITI‐IS, the phase 2 success rate was 44.4%, but would increase to 63.6% if the 14 patients with historic peak inhibitor titer ≥100 BU (and having phase 2 success rate of only 14.3%) were excluded. One patient developed repeated infection after IS treatment. Relapse occurred in 11.4% (4/35) patients with phase 2 success associated with rapid ITI dose reduction or irregular post‐ITI FVIII prophylaxis. Our strategy reduced the cost from high‐dose ITI by 74% to 90%. ConclusionThe use of low‐dose ITI with or without immunosuppressants according to ITI prognostic risk(s) is a clinically and economically feasible strategy for eradicating inhibitors in children with HA, particularly for those with historic peak inhibitor titer <100 BU.

Inappropriate Prescribing of Proton Pump Inhibitors in Children: Insights from a Survey.

Inappropriate Prescribing of Proton Pump Inhibitors in Children: Insights from a Survey.

Treatment of Cardiac Rhabdomyomas with mTOR Inhibitors in Children with Tuberous Sclerosis Complex-A Systematic Review.

Background: Cardiac rhabdomyomas (CRs) are the earliest sign of tuberous sclerosis complex (TSC). Most of them spontaneously regress after birth. However, multiple and/or large tumors may result in heart failure or cardiac arrhythmia. Recently, the attempts to treat CRs with mTOR inhibitors (mTORi) have been undertaken. We reviewed the current data regarding the effectiveness and safety of mTORi in the treatment of CRs in children with TSC. Methods: The review was conducted according to the PRISMA guidelines. Medline, Embase, Cochrane library, and ClinicalTrial.gov databases were searched for original, full-text articles reporting the use of mTORi (everolimus or sirolimus) in the treatment of CRs in children with TSC. Results: Thirty articles describing 41 patients were identified (mostly case reports, no randomized or large cohort studies). Thirty-three children (80.5%) had symptomatic CRs and mTORi therapy resulted in clinical improvement in 30 of them (90.9%). CRs size reduction was reported in 95.1%. Some CRs regrew after mTORi withdrawal but usually without clinical symptoms recurrence. The observed side effects were mostly mild. Conclusions: mTORi may be considered as a temporary and safe treatment for symptomatic CRs in children with TSC, especially in high-risk or inoperable tumors. However, high-quality, randomized trials are still lacking.

Proton pump inhibitors in children: increased risk of asthma

Proton pump inhibitors in children: increased risk of asthma

Psoriasis Associated With Tumor Necrosis Factor Inhibitors in Children With Inflammatory Diseases.

To estimate the incidence rate (IR) of psoriasis in children with inflammatory bowel disease (IBD), juvenile idiopathic arthritis (JIA), and chronic noninfectious osteomyelitis (CNO) with tumor necrosis factor inhibitor (TNFi) exposure as compared to children without TNFi exposure and to the general pediatric population. This was a single-center retrospective cohort study of children with IBD, JIA, or CNO from 2008 to 2018. TNFi exposure was defined as a prescription for adalimumab, etanercept, infliximab, certolizumab, or golimumab, and the primary outcome was incident psoriasis. IRs and standardized incidence ratios (SIRs) were calculated. Cox proportional hazards models were used to assess the association of psoriasis with TNFi exposure and other risk factors. Of the 4,111 children who met inclusion criteria, 1,614 (39%) had TNFi exposure and 2,497 (61%) did not, with 4,705 and 6,604 person-years of follow-up, respectively. There were 58 cases (IR 12.3 per 1,000 person-years) and 25 cases (IR 3.8 per 1,000 person-years) of psoriasis in children with and without TNFi exposure, respectively. The SIR was 18 (95% confidence interval [95% CI] 15-22) overall, 30 (95% CI 23-39) for children with TNFi exposure, and 9.3 (95% CI 6.3-14) for children without TNFi exposure. The hazard ratio of psoriasis comparing TNFi exposure to no TNFi exposure was 3.84 (95% CI 2.28-6.47; P < 0.001). Children with IBD, JIA, and CNO had an increased rate of psoriasis compared to the general pediatric population, with the highest rate in those with TNFi exposure.

ЕФЕКТИВНІСТЬ ЗАСТОСУВАННЯ ІНГІБІТОРІВ ПРОТОННОЇ ПОМПИ У ДІТЕЙ З БРОНХІАЛЬНОЮ АСТМОЮ, ЩО ПОЄДНАНА З ГАСТРОЕЗОФАГЕАЛЬНОЮ РЕФЛЮКСНОЮ ХВОРОБОЮ ТА РЕФЛЮКС-ЕЗОФАГІТОМ

EFFICACY OF PROTON PUMP INHIBITORS IN CHILDREN WITH ASTHMA COMBINED WITH GASTROESOPHAGEAL REFLUX DISEASE AND REFLUX ESOPHAGITIS Yu. G. Antipkin, V. F. Lapshin, T. R. Umanets, А. А. Buratynska, N. G. Chumachenko, L. S. Stepanova, S. I. Tolkach O. Lukyanova Institute of Pediatrics, Obstetrics and Gynecology National Academy of Medical Sciences of Ukraine, Kyiv, Ukraine Abstract. The most common comorbid pathology in children with asthma is gastroesophageal reflux disease associated with reflux esophagitis, which ranges from 32 % to 80 %. To date, the effectiveness of proton pump inhibitors in this category of children and their effect on the level of asthma control remains controversial. The aim is to study the effectiveness of treatment with proton pump inhibitors in children with asthma, combined with gastroesophageal reflux disease and reflux esophagitis. Materials and methods. Forty-six children aged 6–17 years with asthma combined with gastroesophageal reflux disease and reflux esophagitis were examined. They were taking omeprazole 20 mg once daily for 4-8 weeks to control the symptoms of gastroesophageal dysfunction. Criteria for the effectiveness of the prescribed treatment were the dynamics of symptoms of gastroesophageal reflux disease and the level of asthma control, which were assessed at 4 and 8 weeks of treatment. Assessment of symptoms of gastroesophageal reflux disease was performed according to the questionnaire. The degree of control of asthma was determined using the Asthma Control Test. Results and discussion. There was a complete regression of symptoms of gastroesophageal reflux disease after 4 weeks of treatment with omeprazole in 40 (87.0 %) patients. Only 6 (46.2 %) patients with severe asthma had episodic symptoms of gastroesophageal dysfunction after 4 weeks of omeprazole treatment that were not recorded at 8 weeks of treatment. An increase in the number of children with controlled asthma was observed with omeprazole treatment, but no significant difference was found. Conclusions. Proton pump inhibitors are effective in controlling the symptoms of gastroesophageal reflux disease in children with asthma, but not likely in the short-term level of asthma control. Key words: asthma, treatment, children, reflux esophagitis, gastroesophageal reflux disease.

Adverse cutaneous effects of mitogen-activated protein kinase inhibitors in children.

Mitogen-activated protein kinase inhibitors (MEKi) are currently used for the treatment of central nervous system tumors in children and have shown promising results. Cutaneous adverse effects are among the most common toxicities described in adults, but few studies exist in pediatric patients. We aimed to describe the cutaneous adverse effects associated with MEKi in pediatric patients. A retrospective study was carried out at our pediatric hospital in Barcelona, Spain, in patients undergoing treatment with MEKi. Sixty-one children between 1 and 18years of age were included. All patients developed cutaneous toxicity. Eczema, hair abnormalities, oral aphthae, and paronychia were among the most common cutaneous side effects. Recognizing skin toxicity in pediatric patients under treatment with MEKi is essential to establishing appropriate education and therapy, thereby improving treatment tolerability and minimizing avoidable interruptions in treatment.

Real-World Experience Using Emicizumab Prophylaxis for Hemophilia a: Single-Center Experience

INTRODUCTION: Emicizumab is a recombinant humanized bispecific antibody that mimics Factor VIII by bridging Factor IXa and X. It is an important breakthrough in the therapeutic armamentarium for Hemophilia A. Recently concluded Phase III HAVEN trials demonstrated that prophylaxis with emicizumab is superior to recombinant Factor VIII (rFVIII). Patients with Hemophilia A with inhibitors had a 79% reduction in the Annualized Bleeding Rate (ABR) while on emicizumab prophylaxis vs other bypassing agents. Patients without inhibitors had a 68% reduction in ABR on emicizumab vs rFVIII prophylaxis. However, there is limited data on its use in the post-marketing era. METHODS: We report our experience with emicizumab in children and adults with Hemophilia A with and without inhibitors at a single Hemophilia Treatment Center. This Northwell IRB approved retrospective analysis (Jan 2017 - Jun 2020) included data from 12 months prior to starting emicizumab prophylaxis RESULTS: A total of 38 patients on emicizumab prophylaxis were included. 35 patients (92.1%) had severe and 3 (7.9%) had moderate Hemophilia A. 11 patients (28.9%) had a FVIII inhibitor. The mean age was 16.4 yrs with 18 patients (47%) below the age of 12 (age limit used in HAVEN trials). 54.1% of patients were Caucasian, 18.9% were Asian and 16.2% were African American. Thirty patients (78.9%) were on prophylaxis with either rFVIII (71.5%) or FEIBA (21.4%) before starting emicizumab. All 38 patients were started on emicizumab with a loading dose of 3 mg/kg once weekly for 4 weeks followed by a maintenance dose of 1.5 mg/kg weekly. The ABR decreased by 52% for inhibitor patients (3.6 events before and 1.7 events after starting emicizumab). Similarly, there was a dramatic 70.6% reduction for non-inhibitor patients (1.5 events before and 0.44 events after starting emicizumab). Patients on emicizumab prophylaxis experienced 35 bleeding events over 24 months. Nine out of these 35 events occurred in one patient alone with a high titer FVIII inhibitor. 56.5% of these events were joint bleeds, 26.1% (muscle bleeds), 13% (soft tissue bleeds) and 4.4% were mucocutaneous bleeds. Barring 2 events, all episodes (93.9%) were managed outpatient. A majority of these bleeds (72.1%) in inhibitor patients were treated with recombinant Factor VIIa (rVIIa, 16-24 doses for documented hemarthroses) and 3.4% were treated with FEIBA after nonresponse to rVIIa (9-15 doses) due to delayed treatment. Remaining non -inhibitor patients were treated with rFVIII (2-5 doses) with a good response. 52 % of these bleeds were trauma-related. Five surgeries were conducted in the inhibitor patients while on emicizumab prophylaxis and none experienced perioperative bleeding. RVIIa was used as a bypassing agent for 2 of these surgeries - a hemispherectomy and a port removal. No bypassing agent was used for the remaining 3 port removals. Five surgeries (1 total knee arthroplasty and 4 port removals) were performed in patients without a FVIII inhibitor. Recombinant Factor VIII was used as the replacement agent and the patient with knee arthroplasty experienced post-operative bleeding. There were no thrombotic episodes or deaths and all but one continued on emicizumab. The patient post knee arthroplasty discontinued emicizumab after recurrent bleeds into the replaced joint despite aggressive replacement with rFVIII and absence of an inhibitor. DISCUSSION: We report a real-world experience on the use of emicizumab prophylaxis for Hemophilia A with and without inhibitors in children and adults with 78.9% of our cohort below the age of 21 years. Our study demonstrated a similar decrease in ABR for non-inhibitor patients comparable to the HAVEN clinical trials. However, our inhibitor patients experienced a lower bleed reduction rate on emicizumab and all patients still experienced a considerable number of trauma-related bleeds (likely due to increased participation of inhibitor patients in sports). Two patients with traumatic muscle/joint bleeds were treated with aPCC due to non-response to rVIIa suggesting the need for early treatment of suspected bleeds on emicizumab. No thrombotic events or thrombotic microangiopathy was observed in our patient cohort. Our data suggest the need for ongoing patient education for early bleed recognition on emicizumab prophylaxis, prompt treatment of breakthrough bleeds and pre-sports prophylaxis with FVIII or bypassing agents. Disclosures Acharya: BPL: Membership on an entity's Board of Directors or advisory committees; Novonordisk: Membership on an entity's Board of Directors or advisory committees; Bayer Pharma Inc.: Research Funding.

JAK Inhibitors for the Treatment of Pediatric Alopecia Areata.

Alopecia areata is a common autoimmune condition that disproportionately affects children and can significantly hinder quality of life. Few safe and effective therapies are available for the treatment of severely affected pediatric patients. JAK inhibitors have been recently established as an effective and well-tolerated therapy in adults, but there are limited data regarding the use of JAK inhibitors to treat alopecia areata in children. Here, we review the available literature regarding the use of JAK inhibitors in children in dermatology and across other medical disciplines.

Abstract IA15: Tissue-agnostic development of TRK inhibitors for pediatric cancer

Abstract Fusions involving in the NTRK1, NTRK2, and NTRK3 genes that encode the TRKA, TRKB, and TRKC neurotrophin receptors (TRK fusions) occur across a wide range of cancers in children and adults. These fusions result in constitutive expression and ligand-independent activation of the TRK kinase. TRK fusions are pathognomonic for certain rare cancers, including infantile fibrosarcoma and cellular congenital mesoblastic nephroma, and occur at a lower frequency across a range of more common cancers in children including soft-tissue sarcomas, gliomas, and leukemias. Recently, larotrectinib was FDA approved for the treatment of TRK fusion solid tumors in children and adults, representing the first kinase inhibitor to receive FDA histology-agnostic approval for the treatment of cancer. This approval was based on a combined analysis of three clinical trials, including an ongoing pediatric phase 1/2 trial that demonstrated a 94% response rate in 34 children with TRK fusion-positive solid tumors. Remarkably, due to nearly concurrent development in pediatrics and adults, more than 30% of the patients with TRK fusion solid tumors treated with larotrectinib on clinical trials to date have been children. Other TRK inhibitors are also in pediatric development, including entrectinib and LOXO-195, and clinical trials of additional agents including repotrectinib are planned. Entrectinib, which also antagonizes ROS1 and ALK, was reported to induce responses in 11/11 children whose tumors harbored fusions of the TRK, ROS1 or ALK genes. LOXO-195 and repotrectinib have the potential to antagonize resistance mutations that can develop during treatment with first-generation TRK inhibitors, and we reported a 45% response rate to LOXO-195 among 20 patients enrolled to either single-patient treatment protocols or an ongoing pediatric and adult phase 1 study who harbored a TRK kinase resistance mutation. In this talk, I will review the data on the use of TRK inhibitors for TRK fusion cancers in children, discuss unanswered questions related to the use of TRK inhibitors in children and planned clinical trials designed to address these, and highlight the challenges and opportunities that arise when studying novel therapies for rare, molecularly defined diseases. Citation Format: Theodore W. Laetsch. Tissue-agnostic development of TRK inhibitors for pediatric cancer [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr IA15.

The use of checkpoint inhibitors in children with non-Hodgkin lymphomas

The majority of children with NHL can be cured with first-line therapy but 10–25% of affected patients develop relapsed or refractory disease (R-R). The prognosis in these cases is unfavorable, no matter what form of modern treatment is adopted. New approaches to the treatment of this small, yet important, group of patients need to be introduced, including, first and foremost, targeted therapy and immunotherapy. As is known, PD-L1 is frequently expressed in non-Hodgkin lymphomas (NHL), which means that the use of checkpoint inhibitors (CPI) is theoretically justified. Objectives: to analyze the results of treatment with checkpoint inhibitors Nivolumab and Pembrolizumab in children with R-R NHL. The study was approved by the Independent Ethics Committee of the I.P. Pavlov First Saint-Petersburg State Medical University. We used CPIs in 8 children with R-R NHL undergoing treatment at the R.M. Gorbacheva Research Institute for Pediatric Oncology, Hematology and Transplantation. The median age was 12 (2–17) years. The distribution of the patients by diagnosis was as follows: primary mediastinal large B-cell lymphoma (PMBCL, n = 3), peripheral T-cell lymphoma (PTCL, n = 2), diffuse large B-cell lymphoma (n = 1), lymphoblastic lymphoma (n = 2). The median number of prior lines of therapy was 3 (1–5), and all patients had received at least 1 line of standard treatment. Refractory NHL was observed in 5 cases, and 3 patients had had multiple relapses (≥ 3). All patients had progression of their primary disease at the time of prescription of the CPI therapy. Nivolumab was administered at a dose of either 1 mg/kg (n = 4) or 3 mg/kg (n = 3) every 2 weeks, Pembrolizumab - at a dose of 2 mg/kg once every 3 weeks (n = 1). The median number of CPI doses received by the patients was 5.5 (2–12). In 5 patients, CPIs were administered as monotherapy, in 3 – in combination with cytostatic agents: FLAG, Gemcitabine and intrathecal triples (n = 1), Brentuximab vedotin (n = 1) and Bendamustine (n = 1). The efficacy of the treatment was evaluated in accordance with the LYRIC criteria. Once remission was achieved, we used hematopoietic stem cell transplantation and/or radiotherapy for consolidation. Response to the CPI therapy was observed in 4 out of 8 patients (complete response – in 2 patients). Interestingly, only patients with PMBCL and PTCL responded to the treatment. At the median follow-up of 368 (36–879) days, 5 patients were alive, with three of them remaining in long-term remission. During the follow-up period, there was only 1 clinically significant complication (cytopenia) that resolved after treatment with glucocorticosteroids. Finally, we would like to point out that this paper is one of the first reports on the successful use of CPIs in children with R-R NHL. PMBCL and PTCL turned out to be responsive to the treatment. This therapy can be used to achieve remission or possibly even cure in children whose only option would be palliative care if they were treated with standard approaches.

Proton Pump Inhibitors in Children: the Good, the Bad, and the Ugly.

The evidence supporting or contesting the prescription of proton pump inhibitors (PPIs) for children and updates on side effects are reviewed. PPIs remain an important therapeutic option for esophagitis and gastritis. However, recent studies demonstrate no benefit when prescribing PPIs for chronic cough, infantile reflux, asthma, or functional gastrointestinal disorders. Recent studies suggest adverse effects on microbiome diversity and immune function, resulting in increased rates of gastrointestinal infections, bone fractures, and atopic disorders. PPIs influence a variety of cell types within the in the innate and adaptive immune systems. PPI prescriptions in children may be indicated for select conditions; however, multiple side effects and immune effects have been described. While most of these side effects are rare and mild, some studies suggest enduring adverse effects. Future studies to elucidate the mechanism behind some of these immune and infectious complications will be beneficial.