Regular prophylaxis with activated prothrombin complex concentrates in pediatric hemophilia.

BACKGROUND: Regular prophylaxis with activated prothrombin complex concentrates (aPCCs) is effective in adult patients with hemophilia with inhibitors; however, data in children are scarce. METHODS: This was a single-center retrospective study at Saitama Children's Medical Center. Patients with severe and moderate hemophilia with inhibitors aged <15 years at the start of aPCCs prophylaxis were included. Medical records were retrospectively reviewed. RESULTS: We treated nine pediatric patients with hemophilia with inhibitors (median age, 1.9 years; age range, 1.3-12.9 years; inhibitor titers before treatment with aPCCs, 5.9-69 BU/mL) using prophylactic aPCCs (doses, 50-100 U/kg; 2-3 times/week). The median prophylactic period was 13 months (range: 5-31 months). The median annualized bleeding rate (ABR) during prophylactic treatment with aPCCs was 2 (range, 0-17). In four patients, ABR was reduced by 19%-100% with prophylactic aPCCs compared to on-demand aPCCs. An adverse effect of treatment was that a patient with hemophilia B developed nephrotic syndrome 34 months after starting regular prophylaxis with aPCCs. CONCLUSIONS: Regular prophylactic aPCCs reduced the ABR even in younger children with hemophilia A and B. Serious adverse events include nephrotic syndrome, which requires caution.

Efficacy of off-the-shelf bone marrow mesenchymal stem cells for pediatric steroid-refractory acute graft-versus-host disease.

Introduction: Temcell is a mesenchymal stem cell (MSC) product approved for steroid-refractory acute graft-versus-host disease (SR-aGVHD) in Japan. However, reports regarding Temcell's efficacy in pediatric patients have been scarce, and the appropriate use of MSC therapy against pediatric SR-aGVHD also remains to be determined. Patients and Methods: We retrospectively assessed a cohort of pediatric patients treated with Temcell for SR-aGVHD following allogeneic hematopoietic transplantation. MSCs were infused intravenously at a dose of 2 × 106 cells/kg according to the manufacturer's instructions. Results: Twelve patients received eighteen cycles of MSC therapy (median age, 10.3 [1.7-17.8] years), with four receiving additional cycles (one cycle: n = 3, three cycles: n = 1). The severity of aGVHD before MSC therapy was grade I-II in three patients and grade III-IV in nine patients (gut stage 3-4, n= 7; liver stage 3-4; n =2). The median number of immunosuppressive therapy regimens received prior to MSC administration was two (range: 1-5). The first MSC cycle displayed the best overall response rate of 83%, including six patients with a complete response (CR) and with a 49% reduction in the mean daily dose of prednisone after eight weeks. The median time to first response was 3.5 days (range: 2-15 days). Two of the four patients who were re-administered MSCs for recurrent or persistent GVHD achieved a CR. The three-year overall survival rate was 69.4%, while the three-year failure free survival (FFS) rate was 22.2%, with a median FFS of 4.9 months. There were no observable side effects of MSC therapy. Conclusions: MSC therapy appears to be an effective and safe treatment for pediatric SR-aGVHD, with a steroid-sparing effect and satisfactory efficacy upon re-administration. Further studies are needed to determine its appropriate combination with additional treatments and the optimal use of re-administration of MSCs.

Scoring system for diagnosis and pretreatment risk assessment of neuroblastoma using urinary biomarker combinations.

The urinary catecholamine metabolites, homovanillic acid (HVA) and vanillylmandelic acid (VMA), are used for the adjunctive diagnosis of neuroblastomas. We aimed to develop a scoring system for the diagnosis and pretreatment risk assessment of neuroblastoma, incorporating age and other urinary catecholamine metabolite combinations. Urine samples from 227 controls (227 samples) and 68 patients with neuroblastoma (228 samples) were evaluated. First, the catecholamine metabolites vanillactic acid (VLA) and 3-methoxytyramine sulfate (MTS) were identified as urinary marker candidates through comprehensive analysis using liquid chromatography-mass spectrometry. The concentrations of these marker candidates and conventional markers were then compared among controls, patients, and numerous risk groups to develop a scoring system. Participants were classified into four groups: control, low risk, intermediate risk, and high risk, and the proportional odds model was fitted using the L2-penalized maximum likelihood method, incorporating age on a monthly scale for adjustment. This scoring model using the novel urine catecholamine metabolite combinations, VLA and MTS, had greater area under the curve values than the model using HVA and VMA for diagnosis (0.978 vs. 0.964), pretreatment risk assessment (low and intermediate risk vs. high risk: 0.866 vs. 0.724; low risk vs. intermediate and high risk: 0.871 vs. 0.680), and prognostic factors (MYCN status: 0.741 vs. 0.369, histology: 0.932 vs. 0.747). The new system also had greater accuracy in detecting missing high-risk neuroblastomas, and in predicting the pretreatment risk at the time of screening. The new scoring system employing VLA and MTS has the potential to replace the conventional adjunctive diagnostic method using HVA and VMA.

Nelarabine-containing salvage therapy and conditioning regimen in transplants for pediatric T-cell acute lymphoblastic leukemia and lymphoma.

Therapy for relapsed or refractory (r/r) T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) in children is challenging, and new treatment methods are needed. We retrospectively analyzed eight patients with r/r T-ALL (five patients) and T-LBL (three patients) who were treated with nelarabine (NEL) plus etoposide, cyclophosphamide, and intrathecal therapy, administered 3 days apart. Five patients achieved a complete response, and the other three achieved a partial response (PR). All patients underwent hematopoietic stem cell transplantation (HSCT) after two cycles of treatment, except for one patient who received one cycle. Three patients who had previously received HSCT were treated with reduced-intensity conditioning regimens, including fludarabine, melphalan, and NEL; one survived for over 5 years after the second HSCT. Grade 2 neuropathy occurred in one patient, but other severe toxicities commonly associated with NEL were not observed during NEL administration in combination with chemotherapy. The 2-year overall survival and event-free survival rates were 60.0% and 36.5%, respectively. The addition of NEL to reinduction chemotherapy was useful in achieving remission and did not lead to excessive toxicity. In addition, a conditioning regimen, including NEL, appeared to be effective in patients who had previously undergone HSCT.

Early chemotherapeutic intervention to avoid thyroidectomy in pediatric Langerhans cell histiocytosis with thyroid involvement accompanying tracheal stenosis: a report of two cases.

Thyroid involvement is rare in pediatric Langerhans cell histiocytosis (LCH). It may cause airway narrowing, leading to acute-onset respiratory distress. Severe cases may require emergent surgical interventions such as thyroidectomy, which should be avoided in children due to higher rates of complication, particularly in infancy. There is currently no consensus on the indications for surgical treatment in LCH with thyroid involvement. In this report, we describe the cases of two children who presented with tracheal stenosis caused by thyroid LCH, both of which were successfully treated by early induction of chemotherapy, and one of which was also treated for a shorter duration. Mutation analysis detected in-frame deletions of BRAF exon 12 in both cases. These cases suggest that timely diagnosis and administration of chemotherapy may alleviate severe airway obstruction and reduce the need for thyroidectomy in pediatric patients with thyroid LCH.

Long-term efficacy and safety profile of splenectomy for pediatric chronic immune thrombocytopenia.

There are few reports of the long-term efficacy of splenectomy in children with immune thrombocytopenia (ITP). In a 33-year period, we performed splenectomies in 23 pediatric patients with ITP at a single institution in Japan. The age at surgery was 5-22 years with a median of 10 years. The follow-up period was 1-141 months with a median of 48 months. Before surgery, we confirmed the presence or absence of the accessory spleen by contrast-enhanced CT scan and we recommended vaccination with pneumococcal vaccine. Four patients underwent laparotomy before 1998, and 19 patients underwent laparoscopic surgery after 1999. Splenectomy showed high efficacy with a partial response rate of 83% and a complete response rate of 74%. Complete response was maintained in 70% of patients until the end of the observation period, and 91% were able to discontinue long-term management drugs such as steroids. No serious complications such as infectious diseases were observed. Although the number of cases here was small, the long-term efficacy and safety of splenectomy makes it a viable option in pediatric ITP despite the existence of newer therapeutic agents. Further research is necessary to compare the long-term efficacy and safety of splenectomy with new therapeutic agents.

Successful perioperative management using prothrombin complex concentrates in patients with severe congenital protein C deficiency.

Perioperative management of severe congenital protein C deficiency remains unestablished. This deficiency is often treated with anticoagulants, such as warfarin. Although anticoagulants need to be perioperatively discontinued, there are few methods for the management of such patients. We adopted a method for administering prothrombin complex concentrates (PCC), which includes intermittent administration of inactive protein C (PPSB-HT), and examined its outcome as a perioperative management approach for severe congenital protein C deficiency. Three patients underwent our perioperative management six times. We monitored activity levels of protein C, factor IX, and so forth. These patients could be perioperatively managed with PCC treatment.

[Thrombopoietin receptor agonists for pediatric refractory chronic immune thrombocytopenia].

Various treatments have been used to treat chronic immune thrombocytopenic purpura in children; however, none of it has been established as the standard of care. The administration of thrombopoietin receptor agonists (TPO-RAs) has been approved as a new treatment option in Japan. In this case series, TPO-RAs were administered to 16 patients (eltrombopag, n=9; romiplostim, n=7). Excluding the data of two patients who underwent splenectomy immediately after starting treatment with these medicines, platelet counts increased to ≥50,000/µl in seven patients. The adverse events recorded were grade 2 liver dysfunction (n=1), according to the common terminology criteria for adverse events version 4, and myelofibrosis (classified as MF1 or mild reticulin fibrosis), as observed on bone marrow biopsy (n=2). We continued the administration of TPO-RAs at the same dose in these patients because the complications they experienced were mild. The risk of adverse events associated with long-term use of TPO-RAs in this pediatric population remains unclear, and a prospective evaluation is needed.

Hematopoietic Cell Transplantation Rescues Inflammatory Bowel Disease and Dysbiosis of Gut Microbiota in XIAP Deficiency.

BACKGROUND: X-linked inhibitor of apoptosis protein (XIAP) deficiency is an infrequent inborn error of immunity that is often associated with refractory inflammatory bowel disease (IBD). The natural course of XIAP deficiency is typically associated with poor prognosis, and hematopoietic cell transplantation (HCT) is the only curative treatment. OBJECTIVE: To study (1) the effect of HCT on patients with XIAP deficiency undergoing HCT, (2) the status of XIAP deficiency-associated IBD after HCT, and (3) the gut microbiota of XIAP deficiency-associated IBD before and after HCT. METHODS: A nationwide survey of patients with XIAP deficiency was conducted. A spreadsheet questionnaire was collected from the physicians. Feces samples collected from the patients before and after HCT and their healthy family members were analyzed. RESULTS: Twenty-six patients with XIAP deficiency underwent HCT by the end of March 2020, and 22 patients (84.6%) survived. All the survivors underwent a fludarabine-based reduced-intensity condition regimen. Acute graft-versus-host disease was observed in 17 patients (65.4%). Nineteen patients experienced refractory IBD before undergoing HCT. IBD improved remarkably after HCT. After HCT, the colonoscopic and pathological symptoms were restored to normal, and the pediatric ulcerative colitis activity index improved significantly. Gut microbiota indicated dysbiosis before HCT; however, it was improved to resemble that of the healthy family members after HCT. CONCLUSIONS: This study revealed that HCT has a favorable outcome for XIAP deficiency. HCT rescues gut inflammation and dysbiosis in patients with XIAP deficiency.

Asian population may have a lower incidence of hip osteonecrosis in childhood acute lymphoblastic leukemia.

Osteonecrosis (ON), a long-term complication of acute lymphoblastic leukemia (ALL) treatment affects patients' quality of life. Although the incidence of any ON, including asymptomatic, was 21.7% among children with ALL in the U.S., the actual incidence and risk factors in Asia remain unknown. For over 11 years, we performed hip magnetic resonance imaging (MRI) screening to detect asymptomatic ON while initiating maintenance chemotherapy in newly diagnosed children with ALL. Overall, 164 of 175 patients underwent hip MRI screening. The incidence of symptomatic or any ON was 3.0% and 11.6%, respectively. Asymptomatic ON in patients < 10 and ≥ 10 years old was 4.0% and 35.9%, respectively (P < 0.001). In multivariate analysis, age ≥ 10 years was the only significant risk factor. Asymptomatic ON with necrosis of > 30% of the epiphyseal surface of the femoral head was detected in four patients (2.4%). All were ≥ 10 years. Three of them progressed to severe symptomatic ON. The incidence of any ON in Asia may be lower than that seen in the only screening study in the U.S. Future studies should clarify factors affecting such regional differences and develop an effective approach to avoid the progression of ON in children with ALL.

[Gilteritinib for pediatric FLT3 internal tandem duplication-positive recurrent acute myeloid leukemia].

Gilteritinib is an FMS-like tyrosine kinase 3 (FLT3) inhibitor that has shown efficacy in patients with refractory or recurrent adult acute myeloid leukemia (AML) with FLT3 mutations. However, there are limited data for pediatric patients treated with this drug. Herein, we report the clinical courses of two children with FLT3-mutated recurrent AML who received gilteritinib. Case 1: An 11-year-old boy with secondary relapsed AML presented with an FLT3 internal tandem duplication (ITD) since the first recurrence. One week after gilteritinib initiation, blasts, which had comprised 90% of the white blood cells before treatment, almost disappeared from the peripheral blood without tumor lysis syndrome. The patient developed multiple adverse effects and died from the disease 2.5 months after gilteritinib initiation. Case 2: A 12-year-old girl diagnosed with AML was positive for FLT3 ITD. She received gilteritinib during her first relapse post-stem cell transplantation. After the drug was administered, the recipient cell counts increased, as determined by molecular tests (i.e., FISH), whereas microscopically, there was a complete response for 5 months with good performance status. Gilteritinib treatment in children with FLT3-mutated recurrent AML is feasible and effective. As a patient experienced several adverse effects with gilteritinib treatment, clinical trials are required to determine the appropriate pediatric dose of this medication.

Successful treatment of acute myeloid leukemia co-expressing NUP98/NSD1 and FLT3/ITD with preemptive donor lymphocyte infusions.

Patients with acute myeloid leukemia (AML) co-expressing NUP98/NSD1 and FLT3/ITD have a dismal prognosis despite undergoing hematopoietic stem cell transplantation (HSCT). There are a few studies on successful treatment of relapsed AML co-expressing NUP98/NSD1 and FLT3/ITD. We report a refractory case of molecular relapse of AML co-expressing NUP98/NSD1 and FLT3/ITD post-matched sibling HSCT. Donor lymphocyte infusion (DLI) at an early stage of post-transplantation resulted in complete molecular remission for 29 months with durable chronic graft-versus-host disease. Our case suggests the clinical efficacy of preemptive DLI following minimal residual disease analysis for the treatment of refractory AML.

Effective treatment of a steroid-induced femoral neck fracture nonunion with a once-weekly administration of teriparatide in a rheumatoid patient: a case report.

INTRODUCTION: Nonunion of femoral neck fractures frequently occurs in elderly patients. In patients with rheumatoid arthritis, reoperation rates after internal fixation of a displaced femoral neck fracture increase by up to 60 %. Revision surgery with arthroplasty is often preferred for nonunion of femoral neck fractures because there are few effective options for conservative treatment. Teriparatide (TPTD) is a human parathyroid hormone analog and the only anabolic drug for the treatment of severe osteoporosis. DISCUSSION: There are two types of treatment regimens using TPTD: a once-daily administration of recombinant type TPTD and a once-weekly administration of a chemically synthesized type. Although there have been some reports showing that the once-daily recombinant type TPTD was effective for nonunion treatment, the effect of a once-weekly administration of the chemically synthesized type of TPTD is unknown. This report shows the efficacy of the chemically synthesized TPTD for the treatment of femoral neck fracture nonunion in a patient with risk factors that include rheumatoid arthritis and steroid intake.