Prognosis of Second Primary Malignancies in Pediatric Acute Lymphoblastic Leukemia Survivors: A Multicenter Study by the Turkish Pediatric Hematology Society.

The improved survival rates of childhood cancers raise the long-term risk of second primary malignancy (SPM) in childhood and adolescent cancer survivors. The intensity of the treatment protocol used, the use of some groups of chemotherapeutics, and radiotherapy were found to be risk factors for the development of second primary malignancies (SPMs). Forty-one patients who developed acute myelocytic leukemia or any solid organ cancer within 25 years of follow-up, after completion of pediatric acute lymphoblastic leukemia (ALL) treatment, were included in the study. The mean duration of initial ALL diagnosis to SPM was 9.3 ± 6.1 years. The 3 most common SPMs were acute myelocytic leukemia, glial tumors, and thyroid cancer. Thirteen (81%) of 16 patients exposed to cranial irradiation had cancer related to the radiation field. In total 13/41 (32%) patients died, and the 5-year overall survival rate was 70 ± 8%. Patients older than 5 years old at ALL diagnosis had significantly worse overall survival than cases younger than 5 years old. In conclusion, children and adolescents who survive ALL have an increased risk of developing SPM compared with healthy populations, and physicians following these patients should screen for SPMs at regular intervals.

Incidence and Management of Thromboembolism in Patients with Acute Leukemia.

Thromboembolic events (TE) in childhood are relatively rare but, serious complications of acute leukemia. The aim was to define the incidence and risk factors of thrombosis in children with leukemias. The electronic files of pediatric denovo/relapsed acute leukemia patients aged below 18 years, treated between 2011 and 2021 were retrospectively evaluated for thrombotic attacks. Thirty out of 469 patients developed 35 thrombotic events. The median age at the time of the TE was 11.8 (2-17.6) years, and the median time from diagnosis to TE was 9 (0-58) months. The frequency of TE was found at 7.4% (n = 35/469). When catheter related (n = 13) events, superficial venous events (n = 10), and arterial central nervous system thrombosis (n = 1) were excluded, the frequency of TE was decreased to 2.3% (n = 11/469). Children older than 10 years old (13.8%; n = 21/152) had significantly higher thromboembolic events than the others (4.4%; n = 14/317) (p = 0.03). The majority of attacks were symptomatic 66% (n = 23/35). The most common complaints were local pain, swelling, and redness 52% (n = 12/23). The majority of attacks in patients with relapsed (75%; 6/8) and newly diagnosed acute lymphoblastic leukemia (40%; 10/25%) developed during the induction phase. Thrombosis recurred in 13.3% (n = 4/30) of cases more than once. Thrombotic attacks were successfully treated with low molecular weight heparin 60% (n = 21/35), and recombinant tissue plasminogen activator 17% (n = 6/35). None of the children were lost due to thrombosis. Thrombosis is an important complication during acute leukemia treatment. Successful results are obtained with early diagnosis and treatment attempts by creating awareness.

Successful Treatment of Central Nervous System Involvement in Posttransplant EBV-related Lymphoproliferative Disease With Intrathecal Rituximab Therapy.

The posttransplant lymphoproliferative disease is a severe cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation. Central Nervous System involvement in EBV-related PTLD is rare, and there is no standard treatment recommendation. We present our patient and discuss other previously reported cases of EBV-associated PTLD with CNS involvement.

The Evaluation of Central Venous Catheter-related Complications in Pediatric Acute Leukemia Patients: Single Center Experience.

Central venous catheters (CVCs) are important for maintenance of childhood leukemia treatment but CVCs may develop complications. The aim of this study was to retrospectively evaluate the CVC-related complication rate, complication types, and outcome in children with acute leukemia. Complications developing in 310 CVCs (ports n=250, Hickman catheters n=60) inserted in 262 patients were evaluated. A total of 225,296 catheter days were screened. Median (range) CVC in-dwelling time was 661.5 (1 to 2636) days. In total, 157 complications developed of which 91 (58%) were infectious complications, 35 (22.3%) were vascular, 19 (12.1%) were surgical, and 12 (7.6%) were mechanical. Hickman catheters had a higher complication rate and were more prone to mechanical complications ( P <0.01) but there was no difference for other complications. A lower absolute neutrophil count at insertion was observed in children with infectious complications ( P <0.01). Seventy-eight of 136 catheters (57.3%) had to be removed prematurely. The overall complication rate was 0.65 per 1000 catheter days. In multivariate analysis, relapse leukemia, Hickman catheter and low absolute neutrophil count increased complication risk by 4.00, 1.97, and 1.92 times, respectively. Five (1.9%) deaths occurred because of catheter complications. Safe use of CVCs can be improved by early detection of complications and an experienced catheter care team.

Invasive Fungal Infections in Children with Leukemia: Clinical Features and Prognosis

Objective: The incidence of invasive fungal infections (IFIs) has increased due to intensive chemotherapy in childhood leukemia. The aim of this study was to evaluate the incidence, risk factors, causative pathogens, and impact on survival of IFIs among pediatric leukemia patients. Materials and Methods: The hospital records of 307 children with acute lymphoblastic leukemia (ALL, n=238), acute myeloid leukemia (AML, n=51), and relapsed leukemia (n=18) between January 2010 and December 2015 were retrospectively evaluated. Results: A total of 1213 febrile neutropenia episodes were recorded and 127 (10.4%) of them were related to an IFI. Of 307 children, 121 (39.4%) developed IFIs. The mean age was significantly older in the IFI group compared to children without IFIs (p<0.001). IFIs were defined as possible, probable, and proven in 73.2%, 11.9%, and 14.9% of the attacks, respectively. Invasive aspergillosis (81.9%) was the most frequent infection, followed by invasive candidiasis (13.4%) and rare fungal diseases (4.8%). The majority of IFI attacks in both ALL and AML occurred during the induction phase. In total, the death rate was 24% and the IFI-related mortality rate was 18%. The mortality rate among children with IFIs was found to be significantly higher than that of children without IFIs (p<0.001). Overall and event-free survival rates at 5 years were also found to be significantly lower in the IFI group (p<0.001). Relapse (odds ratio: 8.49) was the most effective risk factor for mortality, followed by developing an IFI episode (odds ratio: 3.2) and AML (odds ratio: 2.33) according to multivariate regression analysis. Conclusion: Our data showed that IFIs were more common in older children. Although proven and probable IFI episodes were more frequently diagnosed in cases of relapse and AML, children with ALL and AML had similar frequencies of experiencing at least one episode Conclusion: Our data showed that IFIs were more common in older children. Although proven and probable IFI episodes were more frequently diagnosed in cases of relapse and AML, children with ALL and AML had similar frequencies of experiencing at least one episode

[Evaluation of Micafungin Use in Children]. / Çocuklarda Mikafungin Kullaniminin Degerlendirilmesi.

Micafungin is recommended especially in patients with liver and kidney failure and in the presence of other side effects due to antifungals apart from its known priority indications such as invasive candidiasis. The aim of this study was to evaluate the children who have received micafungin treatment. In the study, 125 children who were hospitalized in the pediatric wards and intensive care units of our hospital and had used micafungin between November 2016 and January 2019 were analyzed retrospectively. Clinical data, micafungin indication, blood values on the first and fourth days of the treatment, side effects of the drug and efficacy were evaluated. Sixty percent (75/125) of the patients were male and the mean age of all the patients were 58 ± 67 (0-215, 30) months. Approximately half of the cases (48%) had malignancy and 13% of them were premature. Sixty-two percent (n= 37) of the malignencies were hematological (27 acute lymphocytic leukemia, nine acute myeloid leukemia, one myelodysplastic syndrome) and 38% (n= 23) were oncological (six neuroblastoma, four Hodgkin lymphoma, two Non-Hodgkin's lymphoma, five sarcomas, one hepatoblastoma, five others) malignencies. The major cause of hospitalization was sepsis (53%). The patients had several risk factors like immunosuppressive therapy (n= 68, 54%), neutropenia (n= 61, 49%), central venous catheter (n= 102, 82%), nasogastric tube (n= 63, 50%), endotracheal intubation tube (n= 49, 39%), urinary catheter (n= 14, 11%) and total parenteral nutrition (n= 81, 65%). Thirteen percent (n= 16) of the cases were post-operative patients. Candida species were cultivated in 97 clinical specimens (blood, endotracheal aspirate, sputum, urine, etc.) among 23 (18%) of the patients. Thirteen (10%) of the patients had candidemia and 62% of them were non-albicans strains. In all candidemias, strains were echinocandin susceptible, and blood cultures were negative within four days. When all the patients (n= 125) were evaluated, a significant decrease in C-reactive protein, an increase in sodium, and a decrease in alanine aminotransferase were observed on the fourth day of micafungin treatment (p<0.05). A total of 39 (31%) patients underwent various antifungal treatments for median seven (1-60) days prior to micafungin treatment. Fourteen (36%) of these 39 patients, had elevated liver function tests (LFT), 10 (26%) of them had hypokalemia, and five (13%) of them had elevated renal function tests. Ten (26%) patients had antifungal-induced hypokalemia previously; and potassium levels were normalized after micafungin treatment (p= 0.0001). The patients for which micafungin treatment was chosen due to elevated liver function tests (n= 47, 38%), whether the antifungalinduced or not; alanine aminotransferase and aspartate aminotransferase levels were decreased after micafungin treatment (p= 0.0001 and p= 0.0001, respectively). Nineteen (15%) of the patients have died within the first 30 days of micafungin treatment and one of them had candidemia. No micafungin treatment related significant side effects were observed in any of the patients. Our study showed that micafungin could be a safe and effective option in pediatric cases including newborns with high liver and kidney function tests.

Cytokine Profile, Apoptosis, Glucocorticoid Receptor, and P-glycoprotein Expression Before and After Megadose Methylprednisolone Treatment in Children With Acute Immune Thrombocytopenia.

OBJECTIVE: Immune thrombocytopenia (ITP) is an autoimmune disease, and it has become evident that T lymphocytes play an important role in the pathogenesis of ITP. We investigated the role of T helper (Th) intracellular IL-2, IL-4, IL-6, IFN-γ, and T lymphocyte apoptosis in the pathogenesis of acute ITP and the effect of glucocorticoid treatment on cytokine profile. We investigated also P-glycoprotein (P-gp) and glucocorticoid receptor (GCR) expression as a possible mechanism for glucocorticoid resistance. MATERIAL AND METHODS: The study includes 20 children with acute ITP having a platelet count <20,000/mm and 20 healthy children as a control group. Patients with acute ITP were treated with megadose methylprednisolone (MDMP) (MDMP in the dose of 30 mg/kg/d between day 1 and 3 and 20 mg/kg/d between day 4 and 7). Th intracellular IL2, IL-4, IL-6, and IFN-γ percentages, T-cell P-gp expression, T-cell and monocyte GCR expression, and T-cell apoptosis were evaluated before and after treatment in acute ITP patients and in the control group. RESULTS: Acute ITP patients had significantly higher Th IL-2, IL-4, IL-6, and IFN-γ percentages compared with the control group (P<0.05). Th IL-2 and IFN-γ percentages were significantly lowered with MDMP treatment (P<0.05). IFN-γ/IL-4 ratio was also lowered with the MDMP treatment (P<0.05). T-lymphocyte P-gp expression and T lymphocyte and monocyte GCR expression were all similar between acute ITP pretreatment and control groups (P>0.05). T-lymphocyte P-gp expression was higher in the posttreatment group than in the pretreatment group (P<0.05). Both T lymphocyte and monocyte GCR expression percentages were not different in the pretreatment and posttreatment groups (P>0.05). Early apoptosis in T lymphocytes was significantly lower in the pretreatment acute ITP group than in the control group (P<0.05). Necrotic apoptosis in T lymphocytes was significantly increased with MDMP treatment (P<0.05). CONCLUSIONS: Th1 and Th2 cytokine profile is observed in acute ITP pathogenesis, and MDMP treatment causes Th1 to Th2 cytokine profile shift and induction of T-lymphocyte apoptosis. There is a need to have a greater number of resistant cases in order to better evaluate the P-gp and GCR expression in glucocorticoid resistance in acute ITP.

Juvenile Myelomonocytic Leukemia in Turkey: A Retrospective Analysis of Sixty-five Patients.

OBJECTIVE: This study aimed to define the status of juvenile myelomonocytic leukemia (JMML) patients in Turkey in terms of time of diagnosis, clinical characteristics, mutational studies, clinical course, and treatment strategies. MATERIALS AND METHODS: Data including clinical and laboratory characteristics and treatment strategies of JMML patients were collected retrospectively from pediatric hematology-oncology centers in Turkey. RESULTS: Sixty-five children with JMML diagnosed between 2002 and 2016 in 18 institutions throughout Turkey were enrolled in the study. The median age at diagnosis was 17 months (min-max: 2-117 months). Splenomegaly was present in 92% of patients at the time of diagnosis. The median white blood cell, monocyte, and platelet counts were 32.9x109/L, 5.4x109/L, and 58.3x109/L, respectively. Monosomy 7 was present in 18% of patients. JMML mutational analysis was performed in 32 of 65 patients (49%) and PTPN11 was the most common mutation. Hematopoietic stem cell transplantation (HSCT) could only be performed in 28 patients (44%), the majority being after the year 2012. The most frequent reason for not performing HSCT was the inability to find a suitable donor. The median time from diagnosis to HSCT was 9 months (min-max: 2-63 months). The 5-year cumulative survival rate was 33% and median estimated survival time was 30±17.4 months (95% CI: 0-64.1) for all patients. Survival time was significantly better in the HSCT group (log-rank p=0.019). Older age at diagnosis (>2 years), platelet count of less than 40x109/L, and PTPN11 mutation were the factors significantly associated with shorter survival time. CONCLUSION: Although there has recently been improvement in terms of definitive diagnosis and HSCT in JMML patients, the overall results are not satisfactory and it is necessary to put more effort into this issue in Turkey.

A National Registry of Thalassemia in Turkey: Demographic and Disease Characteristics of Patients, Achievements, and Challenges in Prevention.

OBJECTIVE: The Turkish Society of Pediatric Hematology set up a National Hemoglobinopathy Registry to demonstrate the demographic and disease characteristics of patients and assess the efficacy of a hemoglobinopathy control program (HCP) over 10 years in Turkey. MATERIALS AND METHODS: A total of 2046 patients from 27 thalassemia centers were registered, of which 1988 were eligible for analysis. This cohort mainly comprised patients with ß-thalassemia major (n=1658, 83.4%) and intermedia (n=215, 10.8%). RESULTS: The majority of patients were from the coastal areas of Turkey. The high number of patients in Southeastern Anatolia was due to that area having the highest rates of consanguineous marriage and fertility. The most common 11 mutations represented 90% of all ß-thalassemia alleles and 47% of those were IVS1-110(G->A) mutations. The probability of undergoing splenectomy within the first 10 years of life was 20%, a rate unchanged since the 1980s. Iron chelators were administered as monotherapy regimens in 95% of patients and deferasirox was prescribed in 81.3% of those cases. Deferasirox administration was the highest (93.6%) in patients aged <10 years. Of the thalassemia major patients, 5.8% had match-related hemopoietic stem cell transplantation with a success rate of 77%. Cardiac disease was detected as a major cause of death and did not show a decreasing trend in 5-year cohorts since 1999. CONCLUSION: While the HCP has been implemented since 2003, the affected births have shown a consistent decrease only after 2009, being at lowest 34 cases per year. This program failure resulted from a lack of premarital screening in the majority of cases. Additional problems were unawareness of the risk and misinformation of the at-risk couples. In addition, prenatal diagnosis was either not offered to or was not accepted by the at-risk families. This study indicated that a continuous effort is needed for optimizing the management of thalassemia and the development of strategies is essential for further achievements in the HCP in Turkey.

Spectral domain optical coherence tomography findings of patients under treatment for pediatric acute lymphoblastic leukemia.

PURPOSE: To investigate the use of spectral domain optical coherence tomography (SD-OCT) findings in pediatric acute lymphoblastic leukemia (ALL) patients. METHODS: Children that were diagnosed with precursor B-cell ALL and classified as belonging to the medium-risk group for relapse were selected for this study. Individuals who were in continuous remission and on maintenance therapy were included in the study group. Cases that had central nervous system involvement were excluded. Age-matched, otherwise healthy children were selected for the control group. Each study participant underwent a comprehensive eye examination and SD-OCT evaluation. Thickness measurements were made within the retinal nerve fiber layer (RNFL), central macula, posterior polar, and peripapillary choroid. RESULTS: A total of 112 eyes of 56 children were included: 54 eyes in the study group and 58 in the control group. Compared to the control group, subfoveal and temporal choroidal thicknesses of the posterior pole were significantly thinner in the study group (P < 0.005). Similarly, peripapillary choroidal thicknesses were significantly thinner in most sectors of the study group (P < 0.005). There were no major differences between groups in terms of central macular thicknesses and overall RNFL thicknesses. CONCLUSIONS: Evidence of choroidal attenuation was found in this subgroup of pediatric ALL patients. Further studies are warranted to clarify the utility of SD-OCT in detecting subclinical ocular involvement and monitoring treatment response and risk of relapse in patients with pediatric leukemia.

Health-Related Quality of Life, Depression, Anxiety, and Self-Image in Acute Lymphocytic Leukemia Survivors.

OBJECTIVE: With increasing survival rates in childhood acute lymphocytic leukemia (ALL), the long-term side effects of treatment have become important. Our aim was to investigate health-related quality of life, depression, anxiety, and self-image among ALL survivors. MATERIALS AND METHODS: Fifty patients diagnosed with ALL and their siblings were enrolled. The Kovacs Children's Depression Inventory, State-Trait Anxiety Inventory, Offer Self-Image Questionnaire, and Pediatric Quality of Life InventoryTM were used for collecting data. ANOVA tests were used to determine if there were any significant differences between groups. RESULTS: ALL survivors had higher depression, more anxiety symptoms, lower quality of life, and more negative self-image when compared to their siblings. CONCLUSION: Continuous diagnostic and interventional mental health services might be necessary for possible emotional side effects of treatment during and after the treatment. Rehabilitation and follow-up programs should be implemented for children during and after treatment for ALL.

Aceruloplasminemia in a Turkish adolescent with a novel mutation of ceruloplasmin gene: the first diagnosed case from Turkey.

Aceruloplasminemia is a rare autosomal recessive disease that affects the iron metabolism of the body. When there is a lack of ceruloplasmin ferroxidase activity, iron accumulates, especially in the brain, pancreas, liver, and retina. The first symptom is generally a persistent hypochromic microcytic anemia with a mild high-serum ferritin level. The affected patients are usually recognized at later ages, when the neurological symptoms appear. The neurological outcome has an adverse effect on the prognosis, which may result in fatality. Therefore, early diagnosis and intervention may prevent a devastating neurological damage. Here, we report a case of aceruloplasminemia in a teenage girl with hypochromic microcytic anemia.