Concurrent Osteonecrosis of the Jaw and Hip in a Child With Severe Aplastic Anemia Undergoing Transplant.

We present the first case of concomitant hip and jaw osteonecrosis in a 10-year-old child with aplastic anemia undergoing a transplant. Biphosphonate treatment may be beneficial for hip osteonecrosis but harmful for jaw osteonecrosis. Our experience suggests that clinicians should be cautious when prescribing bisphosphonate to children with simultaneous hip and jaw osteonecrosis. They should be aware of the osteonecrosis locations and treatment choices.

The Prevalence, Risk Factors and Cardiometabolic Complications of Obesity in Childhood Survivors of Acute Lymphoblastic Leukemia.

Prevalence, risk factors and metabolic complications of overweight/obesity (OW/OB) are not well described in the childhood survivors of acute lymphoblastic leukemia (ALL). Longitudinal changes in body mass index-z score (BMIz) from diagnosis to the last follow-up visit after the end of treatment were evaluated in 73 children at first complete remission. Of them, 40 were tested for adipokine profiles at visit. The mean BMIz increased gradually from diagnosis (0.07 ± 1.68) to the end of dexamethasone containing reinduction therapy (0.70 ± 1.48, P:0.007), followed by a fall at the end of treatment (0.15 ± 1.24) and a rise again at visit (0.40 ± 1.23, P:0.007). OW/OB percentage of 15% at diagnosis, increased to 35% at visit (p < 0.05). Post-treatment OW/OB in survivors was related with being OW/OB at diagnosis (OR 5.4, 95% CI [0.94-31.7]; P = 0.02) and after dexamethasone containing reinduction therapy (OR 5.1, 95% CI [1.1-21.4]; P = 0.05), but not with age at diagnosis, gender, treatment intensity and cranial irradiation. Metabolic syndrome (MetS) was more prevalent in survivors (13%) than in Turkish children (2%). As compared with controls, survivors had higher leptin level (8.1 ± 8.6 vs 3.2 ± 2.2 ng/ml, P = 0.01) and leptin/adiponectin ratio (2.1 ± 3.5 vs 0.6 ± 0.5, P = 0.03). Leptin/adiponectin ratio was correlated with HOMA-IR (r: 0.57, P = 0.001). The prevalence of OW/OB and MetS are elevated in the childhood survivors of ALL. Post-treatment OW/OB in survivors is related with OW/OB at diagnosis and dexamethasone containing therapy. Elevated leptin level and leptin: adiponectin ratio may serve as an early sign of metabolic derangement increasing the risk for early cardiovascular disease.

Allogeneic Hematopoietic Stem Cell Transplantation-Induced Anaphylaxis in 2 Pediatric Cases.

Hematopoietic stem cell transplantation is a curative treatment for many malignant and nonmalignant diseases in children and adults. It is performed with peripheral blood stem cells, bone marrow, and umbilical cord blood. Anaphylaxis may occur during hematopoietic stem cell transplantation, similar to that shown with blood transfusions. In children, although a few cases of anaphylaxis have been reported with cord blood transplantation, no cases of anaphylaxis have been reported with other hematopoietic stem cell transplantations. In this case report, we present the cases of 2 children, one diagnosed with thalassemia major and the other with aplastic anemia, both of whom developed anaphylaxis associated with bone marrow transplantation products cryopreserved with dimethyl sulfoxide and hydroxyethyl starch. Hematopoietic stem cell transplantation-induced anaphylaxis could be associated with cryoprotective agents, especially dimethyl sulfoxide, and alloantigens. In both anaphy-lactic reactions, dimethyl sulfoxide was thought to be the trigger, but it could not be excluded that it was related to stem cell components, plasma, or hydroxyethyl starch.

Sirolimus is effective and safe in childhood relapsed-refractory autoimmune cytopenias: A multicentre study.

Autoimmune cytopenias are a heterogeneous group of disorders characterized by immune-mediated destruction of haematopoietic cell lines. Effective and well-tolerated treatment options for relapsed-refractory immune cytopenias are limited. In this study, the aim was to evaluate the efficacy and safety of sirolimus in this disease group within the paediatric age group. The study enrolled patients in the paediatric age group who used sirolimus with a diagnosis of immune cytopenia between December 2010 and December 2020, followed at six centres in Turkey. Of the 17 patients, five (29.4%) were treated for autoimmune haemolytic anaemia (AIHA), six (35.2%) for immune thrombocytopenic purpura (ITP) and six (35.2%) for Evans syndrome (ES). The mean response time was 2.7 months (range, 0-9 months). Complete response (CR) and partial response (PR) were obtained in 13 of 17 patients (76.4%) and nonresponse (NR) in four patients (23.5%). Among the 13 patients who achieved CR, three of them were NR in the follow-up and two of them had remission with low-dose steroid and sirolimus. Thus, overall response rate (ORR) was achieved in 12 of 17 patients (70.5%). In conclusion, sirolimus may be an effective and safe option in paediatric patients with relapsed-refractory immune cytopenia.

Influence of invasive aspergillosis during acute leukaemia treatment on survival after allogeneic stem cell transplantation: a prospective study of the EBMT Infectious Diseases Working Party.

Background: Infections are the main reason for mortality during acute leukaemia treatment and invasive aspergillosis (IA) is a major concern. Allogeneic stem cell transplantation (alloSCT) is a standard therapy and often is the only live-saving procedure in leukaemia patients. The profound immunodeficiency occurring after alloSCT led to high IA-associated mortality in the past. Therefore, patients with IA were historically considered transplant-ineligible. Recently, there has been improvement of anti-fungal management including novel anti-fungal agents. As a result, more leukaemia patients with IA are undergoing alloSCT. Outcome has not been prospectively assessed. Methods: We performed a prospective study in acute leukaemia patients undergoing alloSCT to analyse the impact of a prior history of probable or proven IA (pre-SCT IA). The primary endpoint was 1-year non-relapse mortality (NRM). Relapse free survival and overall survival were analysed as secondary endpoints. Findings: 1439 patients were included between 2016 and 2021. The incidence of probable or proven pre-SCT IA was 6.0% (n = 87). The cumulative incidence of 1-year NRM was 17.3% (95% CI 10.2-26.0) and 11.2% (9.6-13.0) for patients with and without pre-SCT IA. In multivariate analyses the hazard ratio (HR) for 1-year NRM was 2.1 (1.2-3.6; p = 0.009) for patients with pre-SCT IA. One-year relapse-free survival was inferior in patients with pre-SCT IA (59.4% [48.3-68.9] vs. 70.4 [67.9-72.8]; multivariate HR 1.5 [1.1-2.1]; p = 0.02). Consequently, 1-year overall survival was lower in patients with pre-SCT IA: (68.8% [57.8-77.4] vs. 79.0% [76.7-81.1]; multivariate HR 1.7 [1.1-2.5]; p = 0.01). Interpretation: Pre-SCT IA remains to be significantly associated with impaired alloSCT outcome. On the other hand, more than two thirds of patients with pre-SCT IA were alive at one year after alloSCT. IA is not anymore an absolute contraindication for alloSCT because the majority of patients with IA who undergo alloSCT benefit from this procedure. Funding: There was no external funding source for this study.

Identifying Risk Factors and Improving Preventive Strategies for Febrile Neutropenia in Children with Leukemia Receiving Ciprofloxacin Prophylaxis

The purpose of this study was to identify risk factors and improve preventive strategies for febrile neutropenia (FEN) in children with leukemia who were receiving ciprofloxacin prophylaxis. The study included 100 children with leukemia [n=80 with acute lymphoblastic leukemia and n=20 with acute myeloblastic leukemia (AML)]. Patients were divided into two groups based on whether they had three or fewer FEN episodes (Group 1) or more than three FEN episodes (Group 2). Group 1 contained 63 (63%) of the 100 patients, while Group 2 contained 37 (37%). Older age (≥7 years), leukemia type, prolonged neutropenia (>10 days), and the presence of neutropenia and hypogammaglobulinemia at diagnosis were all risk factors for having more than three FEN episodes. Our findings suggest that, in addition to ciprofloxacin prophylaxis, identifying risk factors and improving preventive strategies could help reduce FEN episodes in children with leukemia.

Occurrence of familial Mediterranean fever in haemophilia patients.

INTRODUCTION: This is the first study of simultaneous occurrences of Familial Mediterranean Fever (FMF) in patients with haemophilia. AIM: The aim was to investigate the frequency and clinical characteristics of FMF in patients with severe haemophilia. METHODS: Our study included 30 patients with severe haemophilia (26 haemophilia A and four haemophilia B). All 30 patients are screened for MEFV genotypes in FMF according to the new Eurofever/PRINTO diagnostic criteria. All cohorts were genetically tested for FMF and thrombophilia. RESULTS: Eight (26%) of 30 haemophilic patients were diagnosed with FMF. Six different heterozygous FMF mutations including M694V (n = 2), E148Q (n = 2), V726A(n = 1), P369S (n = 1), E148Q/K695R (n = 1) and E148Q/M694I (n = 1) were identified. Seven had haemophilia A and only one had haemophilia B. Four (50%) patients had a positive family history and three of them had extraarticular findings specific to FMF. Only one haemophilia B patient received colchicine. Target joints in the knee, ankle, and elbow were identified in three FMF patients. The number of target joints in eight patients with FMF was significantly lower than in twenty-two patients without FMF (p < .05). The annual number of suspected joint bleedings in FMF patients admitted to the hospital was 40; however, 15 (37.5%) were documented bleedings in ultrasounds. Hereditary thrombophilia was detected in seven of eight patients. CONCLUSION: Our data indicate that screening for FMF may be useful in patients with haemophilia who develop arthritis without prominent bleeding and have a positive family history in many Mediterranean countries, including Turkey.

Persistent Rhinovirus Infection in a Child With Leukemia.

Human Rhinovirus (HRV) is one of the most common pathogens causing acute respiratory tract infections in infants and children. Several reports suggest that HRV has the potential to cause chronic infection after an acute viral infection in an immunosuppressed patient. Although chronic HRV infection has been reported in lung transplant recipients, patients with hypogammaglobulinemia and cystic fibrosis, the duration and severity of HRV infection remain unclear. In this study, we present a case of persistent HRV infection in a stem cell transplanted leukemia patient. This report raises several questions regarding the risk factors, duration, and severity of persistent HRV infection in acute leukemia patients, which warrants prospective and longitudinal studies.

Central Nervous System Fungal Infections in Children With Leukemia and Undergoing Hematopoietic Stem Cell Transplantation: A Retrospective Multicenter Study.

BACKGROUND: Central nervous system fungal infections (CNSFI) are seen in patients with hematologic malignancies and have high morbidity and mortality. Because of their rarity, there is limited data on CNSFI in children with no established treatment protocols or guidelines. MATERIALS AND METHODS: In this multicenter retrospective study, 51 pediatric patients with leukemia, 6 of whom had undergone bone marrow transplantation, with proven or probable CNSFI were evaluated. Fungal infections were defined as proven or probable based on European Organisation for Research and Treatment of Cancer criteria. Proven CNSFI was diagnosed by appropriate central nervous system (CNS) imaging or tissue sample findings in combination with positive microbiological results of cerebrospinal fluid. A positive culture, microscopic evidence of hyphae, a positive result of the galactomannan assays are defined as positive microbiological evidence. Probable CNSFI was defined as appropriate CNS imaging findings together with proven or probable invasive fungal infections at another focus without CNS when there is no other explanatory condition. Data was collected by using the questionnaire form (Supplemental Digital Content 1, http://links.lww.com/JPHO/A541 ). RESULTS: Seventeen patients had proven, 34 patients had probable CNSFI. Headaches and seizures were the most common clinical findings. The median time between the onset of fever and diagnosis was 5 days. The most common fungal agent identified was Aspergillus . Sixteen patients received single-agent, 35 received combination antifungal therapy. Surgery was performed in 23 patients. Twenty-two patients (43%) died, 29 of the CNSFI episodes recovered with a 20% neurological sequelae. CONCLUSION: CNSFIs should be considered in the differential diagnosis in patients with leukemia and refractory/recurrent fever, headache, neurologicalocular symptoms, and a radiologic-serological evaluation should be performed immediately. Early diagnosis and prompt management, both medical and surgical, are essential for improving clinical outcomes.

Prognostic role of serum cytokines and soluble HLA-G levels in children with leukemia who undergo allogeneic stem cell transplantation.

This is the first study to have investigated the prognostic role of cytokines and soluble human leukocyte antigen-G (sHLA-G) levels in pediatric leukemia patients who have undergone allogeneic stem cell transplantation (allo-SCT). Forty-one patients with acute leukemia (n = 28, acute lymphoblastic leukemia (ALL) and n = 13, acute myeloblastic leukemia) were recruited. Patients were examined at diagnosis (n = 26), in the pre-transplantation period (PreTx) (n = 26), on the day of transplantation (Tx0) (n = 41), and on post-transplantation Days 14 (PostTx14) (n = 41) and 28 (PostTx28) (n = 41). Serum levels of pro-inflammatory cytokines (interleukin [IL]-1, IL-2, IL-6, Tumor necrosis factor [TNF]-α), anti-inflammatory cytokines (IL-4, IL-10), and sHLA-G were measured by Enzyme-Linked ImmunoSorbent Assay. Median levels of all cytokines tested and sHLA-G were significantly higher at diagnosis and at the post-transplant time points than at PreTx (all p < 0.05). At the time of diagnosis (specifically ALL) and at PostTx14, elevated IL-4, IL-10, and/or sHLA-G were associated with higher post-transplant relapse rates (all p < 0.05). Elevated IL-2 and TNF-α at Tx0 were associated with lower survival rates (both p < 0.05). Levels of serum cytokines and sHLA-G may be useful predictors of survival and relapse in pediatric leukemia patients who undergo allo-SCT.

Assessment of Minimal Residual Disease in Childhood Acute Lymphoblastic Leukemia: A Multicenter Study From Turkey.

Assestment of minimal residual disease (MRD) in childhood acute lymphoblastic leukemia (ALL) is of utmost importance both for risk classification and tailoring of the therapy. The data of pediatric ALL patients that received treatment with Berlin-Frankfurt-Münster (BFM) protocols were retrospectively collected from 5 university hospitals in Turkey. Of the 1388 patients enrolled in the study 390 were treated according to MRD-based protocols. MRD assestment was with real time quantitative polymerase chain reaction (qPCR) in 283 patients and with multiparametric flow cytometry (MFC)-MRD in 107 patients. MRD monitoring had upstaged a total of 8 patients (2%) from intermediate risk group to high-risk group. Univariate analysis revealed age 10 years or above, prednisone poor response, PCR-MRD ≥10-3 on day 33 and on day 78 as poor prognostic factors affecting event-free survival (EFS). Detection of >10% blasts on day 15 with MFC (MFC-high-risk group) was not shown to affect EFS and/or overall survival (log-rank P=0.339). Multiple logistic regression analysis revealed PCR-MRD ≥10-3 on day 78 as the only poor prognostic factor affecting EFS (odds ratio: 8.03; 95% confidence interval: 2.5-25; P=0.000). It is very important to establish the infrastructure and ensure necessary standardization for both MRD methods for optimal management of children with ALL.