Search

Background Diamond-Blackfan anemia (DBA) is an inherited bone marrow failure syndrome characterized by anemia, short stature, congenital anomalies, and cancer predisposition. Most cases are due to mutations in genes encoding ribosomal proteins (RP) leading to RP haploinsufficiency. Effective treatments for the anemia of DBA include chronic red cell transfusions, long-term corticosteroid therapy, or hematopoietic stem cell transplantation. In a small patient series and in animal models, there have been hematologic responses to L-leucine with amelioration of anemia. The study objectives of this clinical trial were to determine feasibility, safety, and efficacy of L-leucine in transfusion-dependent patients with DBA. Procedure Patients ≥2 years of age received L-leucine 700 mg/m2 orally three times daily for nine months to determine a hematologic response and any improvement in growth (NCT01362595). Results This multicenter, phase I/II study enrolled 55 subjects; 43 were evaluable. There were 21 males; the median age at enrollment was 10.4 years (range, 2.5-46.1 years). No significant adverse events were attributable to L-leucine. Two subjects had a complete erythroid response and five had a partial response. Nine of 25, and 11 of 25, subjects experienced a positive weight and height percentile change, respectively, at the end of therapy. Conclusions L-leucine is safe, resulted in an erythroid response in 16% of subjects with DBA, and led to an increase in weight and linear growth velocity in 36% and 44% of evaluable subjects, respectively. Further studies will be critical to understand the role of L-leucine in the management of patients with DBA.

Background Successful treatment of both pediatric autoimmune hemolytic anemia (AIHA) and immune thrombocytopenic purpura (ITP), specifically those that are refractory to first-line therapies, remains unsatisfactory in terms of long-term remission and medication side effects. Here, we propose a novel combination therapy of mycophenolate mofetil (MMF), an adjunct immunosuppressive, and short-term corticosteroids for the treatment of persistent or chronic autoimmune cytopenias in children. This combination may allow for rapid decrease of steroid usage as well as prolonged count stabilization with minimal toxicity to the patient. Procedure Prospective case series of nine patients, six with persistent or chronic ITP and three with persistent or chronic AIHA, between the ages of 5 and 19 years who are being treated with combination therapy consisting of corticosteroids and MMF. Results All patients with ITP (Patients 4–9) and AIHA (Patients 1–3) met complete response (CR) criteria, as they all initially achieved platelet counts 100 × 109 l–1 or more or hemoglobin level greater than or equal to 10 g/dl, respectively, while on combination therapy and then maintained this level or higher while on MMF alone after steroids were discontinued. Conclusions Our results are very promising, as MMF appears to be an effective and well-tolerated adjunct immunosuppressant that allows for rapid weaning of steroid usage, minimal adverse side effects to the patients, and long-term stabilization of counts, a goal that has not been achieved successfully with other secondary treatment modalities. Therefore, this novel combination therapy may be an excellent alternative for the treatment of persistent or chronic autoimmune cytopenias in the pediatric population.

Diamond Blackfan anemia (DBA) is a rare, inherited bone marrow failure syndrome characterized by anemia, congenital anomalies and a predisposition to cancer. The patients usually present during infancy or early childhood, but can also present in adulthood. In the majority of cases DBA is due to a mutation in a small or large ribosomal protein (RP) subunit leading to RP haploinsufficiency. The only treatments for the anemia of DBA are red cell transfusions (accompanied by iron chelation), oral corticosteroid therapy or stem cell transplantation. Pospisilova et al. (Haematologica 2007; 92(5):e66-67) reported one complete and two partial erythroid responses after the use of the branched chain amino acid L-leucine in 6 select patients. In skeletal muscle, leucine supplementation can upregulate components of the protein synthetic machinery, including ribosomal proteins, promoting protein translation. Mouse and fish models of DBA respond with amelioration of anemia to L-leucine. We therefore proposed to study the effect of L-leucine on transfusion dependence and growth in subjects with DBA. Methods: The primary objectives were to determine the feasibility of administering L-leucine in subjects with DBA who are red cell transfusion-dependent and to determine the efficacy of L-leucine to produce a hematologic and growth response. The secondary objective was to determine the safety profile of L-leucine. Twelve study sites were involved in this multi-center, Phase I/II study with an anticipated accrual of 50 subjects. A dose of 700 mg/M2 orally three times per day for 9 months was used. Inclusion criteria included age > 2 years, the diagnosis of DBA and transfusion dependence with adequate kidney and liver function. Response was evaluated at 9 months with Complete Response (CR) defined as no further transfusions required and Hb >9; Partial Response (PR): Hb < 9 gm/dL with an increase in reticulocyte count and transfusion interval; and No Response (NR): no change in transfusion needs, Hb or reticulocyte count . Growth percentiles were evaluated at baseline and at completion of 9 months of treatment and the growth velocity change was calculated. Results: The study opened July 2014 and closed February 2017; 55 subjects were consented; 12 were screen failures; 43 subjects were evaluable. There were 21 males; the median age was 9 years 1 month (2 years 5 months - 46 years 1 month). There were no untoward side effects experienced by any subject that were attributable to the L-leucine. Two subjects had an erythroid CR and 1 subject had a PR. The CRs occurred at 1 month and 3 months after start of L-leucine. The subject with PR had an elevated reticulocyte count but was not able to maintain a Hb >9 gm/dL without a transfusion and thus was not transfusion independent. Of the 30 subjects with growth potential who received L-leucine 10 experienced a positive growth velocity change at 9 months of therapy compared to baseline. At a median age of 7.5 years, the mean pre-leucine height percentile was 27 +/- 17.9 and the post-leucine height percentile was 35 +/- 19.9 (p Conclusions: The administration of L-leucine is safe. L-leucine administration resulted in an erythroid response in 7% of subjects and an increased growth velocity in 33% of growing subjects. Based upon extrapolation from animal models, it is likely that this dose was suboptimal. We hypothesize that higher doses of L-leucine will lead to hematologic responses in more subjects who are transfusion dependent. The potential benefit of added growth in children with DBA may improve final adult height. Disclosures Glader: Agios: Consultancy, Research Funding.

Background Delta granule storage pool deficiency (δ-SPD) is a rare platelet disorder in which a deficiency of platelet granules leads to poor aggregation, resulting in varying clinical bleeding phenotypes. Children with δ-SPD have variable laboratory results, making the proper diagnosis and evaluation controversial. Objectives To describe the demographic and laboratory trends of this population and to assess the value of electron microscopy in diagnostic evaluation and its correlation to bleeding symptoms. Methods We performed a retrospective review of 109 pediatric patients diagnosed with δ-SPD. We collected demographic information and bleeding scores using a validated bleeding assessment tool. A descriptive and exploratory analysis was performed. Results The majority of patients were female, with an average age at diagnosis of 11.61 years. Females were diagnosed at a significantly older age presenting most often with menorrhagia, while males presented most commonly with epistaxis. The majority showed normal lumiaggregometry, the mean platelet electron microscopy (PEM) value was 2.37, and the mean bleeding score was 6. Bleeding assessment tool and PEM had a significantly weak correlation. Conclusions Patients with more dense granules per platelet had higher bleeding scores than those with fewer dense granules per platelet. The current body of evidence does not favor the use of PEM in routine clinical practice, and results are difficult to interpret. In patients with severe mucocutaneous bleeding symptoms and normal platelet aggregation studies, consideration should be given to an alternative diagnosis and further evaluation is warranted.

BACKGROUND Erythrocytapheresis procedures are increasingly used in sickle cell disease. Serum ferritin and noninvasive magnetic resonance imaging measurements of liver iron concentration (LIC) are frequently used to monitor iron overload secondary to hypertransfusion. There is a paucity of data describing the impact of long-term erythrocytapheresis (LTE) on LIC. MATERIALS AND METHODS We measured magnetic resonance imaging liver and cardiac iron on LTE subjects and stratified them into 2 groups: higher LIC (>3 mg/g) and lower LIC (

Central vein thrombosis as a cause of chylothorax is uncommon, and in a few cases in the literature was related to thrombotic complications of central venous access devices (CVAD). Superior vena cava (SVC) occlusion-induced chylothorax has been described in adult sickle cell disease (SCD) in a setting of chronic indwelling CVAD. There are limited reports on chylothorax induced by central venous thrombosis secondary to chronic CVAD in children with SCD. We describe an 8-year-old male patient, with a history of SCD, maintained on long term erythrocytapheresis for primary prevention of stroke, and whose clinical course was complicated by chylothorax which was successfully treated with a pleuroperitoneal shunt.

Context Early and aggressive use of hydroxyurea (HU) in sickle hemoglobinopathies has been in practice at our comprehensive sickle cell center since 2012 when standardized protocols were still evolving. The consensus treatment protocol for hydroxyurea therapy in sickle cell disease (SCD) documented in the "Evidence-Based Management of Sickle Cell Disease: Expert Panel Report, 2014" has authenticated our clinical practice. Objectives Although emergency departments play an important role in providing acute and urgent care for patients with SCD, the frequency of visits by patients can possibly be reduced by increased use of sickle-directed therapies in the outpatient setting. The objective of this study was to determine the impact of aggressive HU therapy, including shared decision making with parents for early use of HU and dose escalation up to the maximum tolerated dose, on the frequency of emergency department (ED) visits for patients with sickle hemoglobinopathies. Methods ED visits by patients with sickle hemoglobinopathies (HbSS disease, Hb S beta zero thalassemia, HbSC disease, Hb S beta plus thalassemia) were identified using ICD-9-CM diagnosis codes of 282.6, 282.60, 282.61, 282.62, 282.63, 282.64, 282.68, 282.69, 282.41, and 282.42. From visits having one or more of these diagnoses, cases that had indicated that the visit was related to an injury, poisoning, or adverse effect of medical treatment were excluded to form the study group of emergency department visits by patients. However, if the ED visit was for HU complications/side effects, they were included. Data from 2010-2015 was collected from the ED of Kosair Children's Hospital and affiliated hospitals in Louisville, which are the community-wide and primary locations where pediatric patients with sickle hemoglobinopathies are evaluated for disease-related complications requiring emergency management including pain crises, fever episodes, acute chest syndrome, etc. To determine if aggressive use of HU was associated with adecrease in the frequency of ED visits, segmented linear regression techniques were used to compare the mean monthly rates of ED visits before and after implementation of this treatment strategy. Results: The rate of sickle hemoglobinopathies seen in the ED significantly decreased after implementation of the aggressive HU treatment protocol (β=2.48 vs. β=-3.91, p=0.003). After implementation of the aggressive HU protocol, there has been a 55% decrease in the monthly rate of sickle hemoglobinopathies seen in the ED (21.0 vs. 9.5, p Conclusion: Substantial reduction in the frequency of ED visits occurred in children with sickle hemoglobinopathies with the simple intervention of early and aggressive usage of HU and its dose escalation to the maximally tolerated dose. The findings of this study suggest that improving the process of prescribing HU as outlined in the "Evidence-Based Management of Sickle Cell Disease: Expert Panel Report, 2014" reduced the complications of sickle hemoglobinopathies requiring emergency care management and is an indicator of the enhanced quality of health care in sickle hemoglobinopathies. Figure 1. The average monthly rate of sickle hemoglobinopathies seen in the ED stratified by year. --- = reference point in which aggressive HU was implemented. Figure 1. The average monthly rate of sickle hemoglobinopathies seen in the ED stratified by year. --- = reference point in which aggressive HU was implemented. Disclosures No relevant conflicts of interest to declare.

Background: Autoimmune cytopenias are defined by immune-mediated destruction of distinct hematopoietic lineages, including white blood cells, red blood cells, and platelets. The destruction of a single lineage in response to an unknown stimulus is known as a primary or idiopathic autoimmune cytopenia. These include immune thrombocytopenia (ITP), autoimmune hemolytic anemia (AIHA), and autoimmune neutropenia (AIN). The primary treatment modality for all autoimmune cytopenias are drugs that suppress or modulate the immune system. Typically first-line treatment involves the use of corticosteroids. However, this treatment modality often requires prolonged use of steroids, which impacts the quality of life of affected patients and causes multiple adverse side effects. For the treatment of pediatric autoimmune cytopenias, the goal of therapy is to modulate the immune system and hence stabilize counts, while also preventing adverse side effects secondary to medications. Mycophenolate mofetil (MMF) is an immunosuppressive drug that inhibits lymphocyte proliferation and limits the mobilization of leukocytes to sites of inflammation. Here, we propose a novel combination therapy of MMF, an adjunct immunosuppressive, and corticosteroids. This combination may allow for rapid decrease of steroid usage as well as prolonged count stabilization in pediatric patients with autoimmune cytopenias. Objective: To evaluate the efficacy of Mycophenolate mofetil and corticosteroids as a novel combination therapy for stabilizing counts and rapid weaning of steroid usage in pediatric patients with autoimmune cytopenias. Design/Method: Prospective case series of 5 patients, 4 with AIHA and 1 with ITP, between the ages of 2 and 16 that are being treated with the combination therapy of corticosteroids and MMF. Results: All patients (Patients 1-4 with AIHA and Patient 5 with ITP) reached minimal to no corticosteroid use after a few months of being on combination therapy, as seen in Figure 1. Patient 1 sustained Hgb levels above 13g/dl after 20 days of combination therapy and an improvement in IgG mediated AIHA, with a decrease in titers from 4+ to 2+ after five months of therapy. In addition, Patient 1 had a decrease in reticulocyte counts from 21.4% to 0.2% after five months of therapy, as well as a decrease in LDH levels from 714 IU/L to 551 IU/L after two months of therapy. Patient 2 sustained Hgb levels above 13g/dl after one month of combination therapy as well as a normal reticulocyte count of 0.8%. Patient 3 has been on combination therapy for one month and has improved Hgb levels from 11g/dl to 11.4g/dl as well as had a significant reduction in steroid usage. Patient 4 sustained Hgb levels above 12g/dl after six months of combination therapy, an improvement in IgG mediated AIHA, with a decrease in titers from 4+ to 3+ after 16 months of therapy, and a decrease in reticulocyte counts from 43.2% to less than 2% after 12 months of therapy. Patient 5 with ITP had a marked increase in platelet counts from 9k/μl to 418k/μl after only 8 days of combination therapy and has maintained normal platelet counts thereafter. All patients have rapidly decreased steroid doses, maintained targeted MMF doses without toxicities or secondary infections, and not had recurrences of autoimmune cytopenias. Conclusions: Mycophenolate mofetil has been utilized as an adjunct immunosuppressive in a small number of autoimmune diseases and for the treatment of graft-versus-host disease in allogeneic hematopoietic stem cell transplantation. Never before has the combination of MMF and corticosteroids been used to treat pediatric patients with autoimmune cytopenias. The novel combination of MMF and corticosteroids may be an optimal treatment option for pediatric patients with autoimmune cytopenias such as AIHA and ITP. This unique combination of high dose steroids with rapid weaning, coupled with the continued use of MMF mediated immunosuppression allows for prolonged count stabilization with minimal adverse side effects. Figure 1: Total daily dose of prednisone vs. months on combination therapy Figure 1:. Total daily dose of prednisone vs. months on combination therapy *Patient 1's baseline total daily dose of prednisone is 120mg at time 0 months Disclosures Off Label Use: Mycophenalate mofetil is an immunosuppressive medication initially utilized in transplantation medicine, and now has been used in a variety of autoimmune diseases. .

Background Tacrolimus is an immunosuppressive drug that is used to lower the activity of the patient’s immune system to prevent organ rejection. Unfortunately, there is limited data regarding the therapeutic equivalency of generic tacrolimus formulations especially in children. We report the case of a pediatric patient having an inability to achieve a therapeutic trough level for tacrolimus after conversion from brand name to the generic formulation. Case presentation A 17-month-old male patient diagnosed with T-cell acute lymphoblastic leukemia underwent allogeneic stem cell transplantation. The patient initially received intravenous (IV) tacrolimus for graft-versus-host disease (GVHD) prophylaxis and achieved therapeutic levels. The patient was then switched to an oral brand formulation of tacrolimus, and was able to maintain trough levels within the therapeutic range. After being discharged, the patient received the generic formulation of tacrolimus from an outside pharmacy and the care team was unable to reach therapeutic levels despite multiple dose escalations. Returning to brand name tacrolimus resulted in prompt achievement of therapeutic levels. Conclusions A likely etiology for the inability to achieve therapeutic trough levels in this patient is the change in formulation from brand formulation to generic version. Other factors including drug-drug interaction, preparation of the medication by a different pharmacy, drug-food interaction and genetic factors were also considered. Physicians and pharmacists must be aware of the inability to achieve targeted therapeutic concentrations of tacrolimus resulting from the conversion of brand name to the generic formulation until these generic formulations are tested in clinical trials in a pediatric population.