The impact of Treosulfan-based conditioning for inborn errors of immunity: Is dose monitoring crucial?

INTRODUCTION: In children with inborn errors of immunity (IEI) who will receive a hematopoietic stem cell transplant (HSCT) treosulfan-based conditioning is currently preferred. The aim of this study was to investigate early and late outcomes in pediatric IEI patients receiving pre-HSCT treosulfan and to examine the effect of treosulfan dose monitoring on outcomes. METHODS: Seventy-three pediatric patients receiving this management between 2015 and 2022 were included. RESULTS: Overall survival rate was 80%, and event-free survival was 67.8%. A larger treosulfan dose AUC after first application increased the rate of early toxicity (p = .034) and slowed lymphocyte engraftment (r = .290; p = .030). Underlying disease, treosulfan AUC, donor type, stem cell type, number of immunosuppressive agents, the dose of anti-thymocyte globulin, and post-transplantation cyclophosphamide did not to increase risk of acute graft-versus-host disease. The risk of mixed chimerism (MC) in patients with autoimmune lymphoproliferative syndrome and leukocyte adhesion deficiency were higher than those with severe combined immunodeficiency (p = .021 and p = .014, respectively). The risk of MC was lower in those receiving peripheral blood stem cells (SC) compared with bone marrow derived SC (OR = .204, p = .022). CONCLUSION: The AUC of the treosulfan dose was not associated with poorer late outcomes. Treosulfan is an agent that can be used safely in the IEI patient group,  level measurement appears essential to identify early toxicities. Prospective studies with more extended follow-up periods are needed.

Primary immunodeficiencies: HSCT experiences of a single center in Turkey.

BACKGROUND: Primary immunodeficiency diseases (PID) are characterized by the occurrence of frequent infections and are caused by many genetic defects. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment option for the majority of PID. As a Pediatric Hematology-Oncology-Immunology Transplantation Unit, we wanted to present our HSCT experience regarding treatment of primary immunodeficiency diseases. METHODS: 58 patients were included in the study between January 2014 and June 2019. We searched 9/10 or 10/10 matched-related donor (MRD) firstly, in the absence of fully matched-related donor. We screened matched unrelated donor (MUD) from donor banks. MRD was used in 24 (41.3%) patients, MUD in 20 (34.4%) patients, and haploidentical donors in 14 (24.1%) patients. Demographic data, HSCT characteristics, and outcome were evaluated. While 16 patients had severe combined immunodeficiency (SCID), the remaining was non-SCID. RESULTS: Of the 58 patients, 38 were male and 20 were female. Median age at transplantation was 12 months (range: 2.5-172 months). Combined immunodeficiencies consisted 67.2% of patients. Mean follow-up time was 27 months (6 months-5 years). Median neutrophil, lymphocyte, and thrombocyte engraftment days were similar in comparison of both donor type and stem cell source. The most common complication was acute GvHD in 15 (25.8%) patients. In total, five patients (31%) belonging to the SCID group and 10 patients (23.8%) belonging to the non-SCID group died. Our total mortality rate was 15 (25.8%) in all patients. CONCLUSIONS: We would like to present our HSCT experiences as a pediatric immunology transplantation center. Existing severe infections before transplantation period, BCGitis, and CMV are important issues of transplantation in Turkey. However, the follow-up time is shorter than some studies, our results regarding complications and survival are similar to previous reports.

Posterior Reversible Encephalopathy Syndrome in Childhood Hematological/Oncological Diseases: Multicenter Results.

The aim of the study was to analyze the characteristics of posterior reversible encephalopathy syndrome (PRES) cases treated at 10 different institutions in our country. Fifty-eight patients diagnosed with PRES were included in this study. The data of PRES cases from 10 departments of pediatric hematology/oncology were analyzed. The mean age of the patients at the time of diagnosis of PRES was 8.95±3.66 years. Most patients (80.4%) had a primary diagnosis of acute leukemia. Patients received chemotherapy (71.4%) and/or used steroids within 14 days before the diagnosis of PRES (85.7%). Hypertension was found in 83.9% of the patients. Twenty-six patients had infections and 22 of them had febrile neutropenia. The most common electrolyte disorders were hypocalcemia, hypomagnesemia, and hypopotassemia. Six patients had tumor lysis syndrome and 4 had inappropriate antidiuretic hormone syndrome. Magnetic resonance imaging was used for diagnosis in all patients. The most commonly involved regions by magnetic resonance imaging were occipital (58%), parietal (51%), and frontal lobes (45%), respectively. Twenty-five patients required intensive care and 7 patients were intubated. In conclusion, PRES may develop during the follow-up and treatment of hematological diseases. In addition to steroid and intense combined chemotherapies, immunosuppressive agents and hypertension are also factors that may be responsible for PRES.

Hepatosplenic Fungal Infections in Children With Leukemia-Risk Factors and Outcome: A Multicentric Study.

BACKGROUND: Invasive fungal infections, including hepatosplenic fungal infections (HSFI), cause significant morbidity and mortality in children with leukemia. There are not enough data to support for the best approach to diagnosis of HSFI in children, nor for the best treatment. PROCEDURE: In this multicentric study, we assessed the demographic data, clinical and radiologic features, treatment, and outcome of 40 children with leukemia and HSFI from 12 centers. RESULTS: All cases were radiologically diagnosed with abdominal ultrasound, which was performed at a median of 7 days, of the febrile neutropenic episode. Mucor was identified by histopathology in 1, and Candida was identified in blood cultures in 8 patients. Twenty-two had fungal infection in additional sites, mostly lungs. Nine patients died. Four received a single agent, and 36 a combination of antifungals. CONCLUSIONS: Early diagnosis of HSFI is challenging because signs and symptoms are usually nonspecific. In neutropenic children, persistent fever, back pain extending to the shoulder, widespread muscle pain, and increased serum galactomannan levels should alert clinicians. Abdominal imaging, particularly an abdominal ultrasound, which is easy to perform and available even in most resource-limited countries, should be recommended in children with prolonged neutropenic fever, even in the absence of localizing signs and symptoms.

Treatment of plasminogen deficiency patients with fresh frozen plasma.

Congenital plasminogen (Plg) deficiency leads to the development of ligneous membranes on mucosal surfaces. Here, we report our experience with local and intravenous fresh frozen plasma (FFP). We retrospectively reviewed medical files of 17 patients and their eight first-degree relatives. Conjunctivitis was the main complaint. Thirteen patients were treated both with intravenous and conjunctival FFP. Venous thrombosis did not develop in any. Genetic evaluation revealed heterogeneous mutations as well as polymorphisms. Diagnosis and treatment of Plg deficiency is challenging; topical and intravenous FFP may be an alternative treatment.

Homozygous protein C deficiency presenting as neonatal purpura fulminans: management with fresh frozen plasma, low molecular weight heparin and protein C concentrate.

Purpura fulminans in neonates is a rapidly progressive thrombotic disorder manifesting as hemorrhagic skin infarction and disseminated intravascular coagulation. Being inherited in an autosomal dominant manner, it is a medical emergency. Clinical presentations of patients may vary depending on the genetic mutations. Retinal and intracranial hemorrhages are the worst clinical scenarios with persistent morbidity. During acute phase, fresh frozen plasma, protein C concentrates and anticoagulant therapy should be administered rapidly. Here we report a patient with homozygous protein C deficiency.

Sinusoidal Obstruction Syndrome During Chemotherapy of Pediatric Cancers and its Successful Management With Defibrotide.

Sinusoidal obstruction syndrome (SOS) is a life-threatening complication generally occurring after hematopoietic stem cell transplantation. SOS after standard dose chemotherapy in malignancies is rare. Between the year 1995 and 2016, 414 patients were diagnosed with acute lymphoblastic leukemia and 113 patients were diagnosed with Wilms tumor in our institution. Among these patients, 4 patients with acute lymphoblastic leukemia (0.96%) and 2 patients with Wilms tumor (1.7%) developed SOS during treatment. SOS behaves like a local disseminated intravascular coagulation. Defibrotide has proved to be effective in SOS. In this article, we report our experience with defibrotide in SOS.

Hemophilia Caregiver Burden in a Low Socioeconomic Region of Turkey.

OBJECTIVE: This study aims to evaluate the caregiver burden of parents of hemophilia patients and related factors in the southeast region of Turkey, where access to a regular healthcare facility is more complicated than in other areas. MATERIALS AND METHODS: Twenty-six caregivers of patients with hemophilia were consecutively enrolled in this non-interventional study. Caregiver burden is measured using the "HemophiliaAssociated Caregiver Burden Scale" (HEMOCAB). RESULTS: Hemophilia affects 65.4% of caregivers emotionally, and 92.3% feel the burden caused by financial problems related to hemophilia. The perception of the patients by caregivers was negative in the groups of low educational degree and unstable employment status (P = .037 and P = .017, respectively). The employment status and job changes influence the caregiver burden because of hemophilia (P = .034 and P = .001, respectively). The groups of those who spent greater than 5 hours for transportation to the hemophilia treatment center (HTC) had a higher burden (P = .001). Multiple linear regression analysis analyzed variables affecting HEMOCAB, frequency, and burden total scores. The model created with the burden total score was statistically significant (P = .047). CONCLUSION: The main factors affecting caregiver burden were educational status, working conditions, and economic difficulties, as well as the length of infusion times and transfer to HTCs. There is a need to develop socioeconomic policies related to these problems.

Restrictive effects of thalassemia on respiratory functions: One center experience.

OBJECTIVE: Respiratory functions in thalassemia major (TM) patients concerning poor chelation are a frequently researched issue. Our study aims to evaluate the lung functions of our patients with TM in the chronic transfusion program and to correlate them with their age, ferritin levels, and pre-transfusion hemoglobin values. METHODS: Height, weight, pulmonary function test (PFT) results, pre-transfusion hemoglobin levels, and ferritin levels of 97 patients (55 boys and 42 girls) without any underlying cardiac or chronic respiratory disease were recorded. PFT is consisted of forced vital capacity (FVC) and forced expiratory volume in one second (FEV1), the ratio of FEV1/FVC to peak expiratory flow (PEF), and forced mid-exhaled flow between 25% and 75% of mid-expiratory flow (MEF25-75). Data were analyzed with IBM SPSS V25. RESULTS: Low FVC was observed in 58 patients (60%), and low FEV1 was observed in 26 patients (27.6%). Low PEF was observed in 62 patients (64.5%), and low MEF25-75 was observed in 8 (8.3%). PFT was affected in 75 patients (78.1%). The pattern of involvement was restrictive. Age, height, and ferritin values significantly affected the MEF25-75 (p<0.05). Age and pre-transfusion hemoglobin values had a significant effect on the FVC test (p<0.05). There was a weak negative correlation between ferritin values and MEF25-75 (r=-0.221) and a weak positive correlation between pre-transfusion hemoglobin and FVC (r=0.222). CONCLUSION: Age and height are the main risk factors affecting FEV1, MEF25-75, and PEF. Serum ferritin has only an effect on MEF25-75 in our study. The respiratory functions of TM patients were affected in a restrictive pattern.

Thrombosis in children: Which test to whom, when and how much necessary?

Pediatric thrombosis is multifactorial, and usually risk factors either congenital or acquired are present. After 2000, systematic reviews and meta-analysis on pediatric venous thromboembolic disease and inherited thrombophilia revealed elevated thrombotic risks in these children. In this review, we discuss thrombosis and new literature in various pediatric patient groups and the usefulness of thrombophilia testing.