Soluble Hemojuvelin and Ferritin: Potential Prognostic Markers in Pediatric Hematopoietic Cell Transplantation.

OBJECTIVE: Iron overload (IO) is a common and life-threatening complication resulting from the therapy of AL and HCT patients. This study aimed to evaluate the prognostic value of 12 serum biomarkers of iron metabolism in pediatric patients treated for AL or undergoing HCT. PATIENTS: Overall, 50 patients with AL after intensive treatment and 32 patients after HCT were prospectively included in the study. AL patients at diagnosis and healthy controls served as reference groups. METHODS: The impact of the following 12 serum iron metabolism parameters on the outcome of AL/HCT patients was analyzed: iron, transferrin (Tf), total iron-binding capacity (TIBC), ferritin, ferritin heavy chains (FTH1), ferritin light chains (FTL), hepcidin, soluble hemojuvelin (sHJV), soluble ferroportin-1 (sFPN1), erythroferrone (ERFE), erythropoietin (EPO), and soluble transferrin receptor (sTfR). RESULTS: With a median follow-up of 2.2 years, high levels of ferritin and low levels of sHJV had an adverse prognostic impact on OS and EFS in children after HCT. If these patients were combined with those with AL after intensive chemotherapy, the results were confirmed for OS and EFS both for ferritin and sHJV. CONCLUSIONS: Among the 12 analyzed serum parameters of iron metabolism, increased levels of ferritin and decreased levels of sHJV had an adverse prognostic impact on survival in children after HCT. More data are needed to clarify the relationship between ferritin, sHJV, and mortality of AL children after intensive chemotherapy, and more extensive prospective studies are required to prove sHJV predictivity.

Unbalance in Iron Metabolism in Childhood Leukemia Converges with Treatment Intensity: Biochemical and Clinical Analysis.

OBJECTIVE: The aim of this study was to evaluate non-transferrin-bound iron (NTBI) and labile plasma iron (LPI) levels and other parameters of iron metabolism in children undergoing therapy for acute leukemia or after hematopoietic cell transplantation (HCT), in the context of iron overload. PATIENTS: A total number of 85 children were prospectively included into four groups: controls, acute leukemia de novo, acute leukemia after intensive treatment, and after HCT. METHODS: The following iron metabolism parameters were analyzed: (1) parameters measuring functional and storage iron pools: NTBI, LPI, iron, transferrin, total iron-binding capacity, ferritin, ferritin heavy and light chains; (2) proteins regulating iron absorption and its release from tissue stores: hepcidin, soluble hemojuvelin, soluble ferroportin-1; (3) proteins regulating the erythropoietic activity of bone marrow: erythroferrone, erythropoietin, soluble transferrin receptor. RESULTS: Intensive treatment of leukemia in children was associated with the presence of serum NTBI and LPI, which was the highest in the HCT group followed by the acute leukemia after treatment and de novo groups. In patients after HCT, the most significant changes were found in NTBI, LPI, iron, ferritin, hepcidin, and ferroportin-1 levels. CONCLUSIONS: The occurrence of NTBI and LPI in the circulation and the intensification of disturbances in iron metabolism were associated with the intensity of the anti-leukemic treatment.

Plerixafor combined with G-CSF for stem cell mobilization in children qualified for autologous transplantation- single center experience.

Failure of autologous peripheral blood CD34+ stem cells collection can adversely affect the treatment modality for patients with hematological and nonhematological malignant diseases where high dose chemotherapy followed by hematopoietic stem cell transplantation has become part of their treatment. Plerixafor in conjunction with G-CSF is approved for clinical use as a mobilization agent. The clinical efficacy of Plerixafor in CD34+ cells collection was analyzed in our institution. A total of 13 patients aged 1-15,5 years received Plerixafor in combination with G-CSF: 7 with neuroblastoma, 2 with Ewing's sarcoma and single patients with Hodgkin's lymphoma, germ cell tumor, retinoblastoma and Wilms tumor. Twelve patients (923%) achieved CD34+ cell counts of ≥ 20 × 106/L after 1-7 doses of Plerixafor. The average 9,9 - fold increase in number of CD34+ cells were achieved following the first dose and 429 - fold after second dose of plerixafor. Among the 13 patients, 12 yielded the minimum required cell collection of 2 × 106/kg within an average of 2 doses of Plerixafor. The mean number of apheresis days was 1.75. The median total number of collected CD34+ cells was 982 × 106/kg. Plerixafor enables rapid and effective mobilization, and collection of sufficient number of CD34+ cells.

Clinical Outcome in Pediatric Patients with Philadelphia Chromosome Positive ALL Treated with Tyrosine Kinase Inhibitors Plus Chemotherapy-The Experience of a Polish Pediatric Leukemia and Lymphoma Study Group.

The treatment of children with Philadelphia chromosome positive acute lymphoblastic leukemia (ALL Ph+) is currently unsuccessful. The use of tyrosine kinase inhibitors (TKIs) combined with chemotherapy has modernized ALL Ph+ therapy and appears to improve clinical outcome. We report herein the toxicity events and results of children with ALL Ph+ treated according to the EsPhALL2010 protocol (the European intergroup study of post-induction treatment of Philadelphia chromosome positive ALL) in 15 hemato-oncological centers in Poland between the years 2012 and 2019. The study group included 31 patients, aged 1-18 years, with newly diagnosed ALL Ph+. All patients received TKIs. Imatinib was used in 30 patients, and ponatinib was applied in one child due to T315I and M244V mutation. During therapy, imatinib was replaced with dasatinib in three children. The overall survival of children with ALL Ph+ treated according to the EsPhALL2010 protocol was 74.1% and event-free survival was 54.2% after five years. The cumulative death risk of the study group at five years was estimated at 25.9%, and its cumulative relapse risk was 30%. Our treatment outcomes are still disappointing compared to other reports. Improvements in supportive care and emphasis placed on the determination of minimal residual disease at successive time points, which will impact decisions on therapy, may be required.

Results of two consecutive treatment protocols in Polish children with acute lymphoblastic leukemia.

The aim of the study was to retrospectively compare the effectiveness of the ALL IC-BFM 2002 and ALL IC-BFM 2009 protocols and the distribution of risk groups by the two protocols after minimal residual disease (MRD) measurement as well as its impact on survival. We reviewed the medical records of 3248 patients aged 1-18 years with newly diagnosed ALL who were treated in 14 hemato-oncological centers between 2002 and 2018 in Poland. The overall survival (OS) of 1872 children with ALL treated with the ALL IC 2002 protocol was 84% after 3 years, whereas the OS of 1376 children with ALL treated with the ALL IC 2009 protocol was 87% (P < 0.001). The corresponding event-free survival rates were 82% and 84% (P = 0.006). Our study shows that the ALL IC-BFM 2009 protocol improved the results of children with ALL compared to the ALL IC-BFM 2002 protocol in Poland. This analysis confirms that MRD marrow assessment on day 15 of treatment by FCM-MRD is an important predictive factor.

First-line treatment failure in childhood acute lymphoblastic leukemia: The polish pediatric leukemia and lymphoma study group experience.

The aim of this study was to evaluate the risk factors of relapse and treatment-related deaths in acute lymphoblastic leukemia (ALL) in children residing in Poland.A total of 1872 patients with newly diagnosed ALL, treated according to the ALL IC-BFM 2002 protocol in 14 Polish pediatric hematology centers from 2002 to 2012 were included in the study. Three-hundred eighty-four patients experienced treatment failure. The last follow-up was 31 December, 2016.Univariate analysis identified factors in each risk group that were significantly different between children whose treatment failed and those who remained in the first remission. Multivariate analysis demonstrated that only the age of 10 years or over at primary diagnosis in the high-risk group was an adverse prognostic factor. To facilitate the analysis, patients were divided into three groups: relapsed children who survived; relapsed children who died; children without relapse who died due to toxicity.Our analysis showed that age older than 10 years is a particular risk factor for the failure of first-line of treatment, both in terms of relapse and treatment-related mortality.

Grade 3 and 4 Toxicity Profiles During Therapy of Childhood Acute Lymphoblastic Leukemia.

BACKGROUND/AIM: The risk factors, clinical features and non-hematological toxicity profiles during chemotherapy in acute lymphoblastic leukemia (ALL) patients treated in pediatric hematology centres were analysed. MATERIALS AND METHODS: A total of 902/1872 children were reported as having grade 3 or 4 toxicity. RESULTS: Among the analysed toxicities, infection and gastrointestinal and liver toxicities were the most common. The median follow-up was 6.8 years. Overall survival and event-free survival rates for the analysed group were lower than those reported for the group without grade ≥3 toxicity. In univariate analysis, we identified the number of toxic episodes, the risk group and remission status that had a significant impact on the outcome. Multivariate analysis demonstrated the risk group and the number of toxic episodes ≥3 to be statistically significant for the results. CONCLUSION: The toxic profiles investigated in our report should be used in future efforts to decrease the burden of side effects during chemotherapy.

Clinical characteristics and analysis of treatment result in children with Ph-positive acute lymphoblastic leukaemia in Poland between 2005 and 2017.

OBJECTIVE: The aim of this study was to analyse the clinical characteristics and outcome of children diagnosed with Ph+ ALL. MATERIAL AND METHODS: A total of 2591 newly diagnosed ALL children were treated in Poland between the years 2005 and 2017. Of those, 44 were diagnosed with Ph(+) ALL. The patients were treated according to protocols: ALL IC-BFM 2002 and 2009 (26 patients), EsPhALL (12 patients), initially ALL IC-BFM and then EsPhALL (6 patients). RESULTS: The median of follow-up in the observed group was 3 years. Overall survival (OS) and event-free survival (EFS) of Ph+ ALL group were 0.73 and 0.64. OS and EFS of patients after HSCT were 0.78 and 0.66, while without HSCT were 0.6 and 0.6, P = 0.27 and 0.63. OS was 0.8 for patients treated with chemotherapy plus imatinib and 0.61 for chemotherapy alone, P = 0.22, while EFS was 0.66 (imatinib therapy) and 0. 61 (without imatinib), P = 0.41. CONCLUSION: Our study suggests that adding imatinib to intensive chemotherapy seems to improve outcome. However, this study was limited by a small number of patients and a variety of chemotherapy regimens with or without imatinib.

Outcome of acute lymphoblastic leukemia in children with down syndrome-Polish pediatric leukemia and lymphoma study group report.

Children with Down syndrome (DS) have a 20-fold increased risk of developing leukemia compared with the general population. The aim of the study was to analyze the outcome of patients diagnosed with Down syndrome and acute lymphoblastic leukemia (ALL) in Poland between the years 2003 and 2010. A total of 1848 children were diagnosed with ALL (810 females and 1038 males). Of those, 41 (2.2%) had DS. The children were classified into three risk groups: a standard-risk group-14 patients, an intermediate-risk group-24, a high-risk group-3. All patients were treated according to ALLIC 2002 protocol. The median observation time of all patients was 6.1 years, and in patients with DS 5.3 years. Five-year overall survival (OS) was the same in all patients (86% vs 86%, long-rank test, p = .9). The relapse-free survival (RFS) was calculated as 73% in patients with DS and 81% in patients without DS during a median observation time (long-rank test, p = .3). No statistically significant differences were found in the incidence of nonrelapse mortality between those two groups of patients (p = .72). The study was based on children with ALL and Down syndrome who were treated with an identical therapy schedule as ALL patients without DS, according to risk group. This fact can increase the value of the presented results.

The Influence of Primary Cytomegalovirus or Epstein-Barr Virus Infection on the Course of Idiopathic Thrombocytopenic Purpura.

Idiopathic thrombocytopenic purpura (ITP) in children is usually triggered by a viral infections such as cytomegalovirus (CMV) or Epstein-Barr virus (EBV) infection. The aim of this study was to assess the frequency of CMV and EBV infections in children with first relapse of ITP, and the influence of these infections on the course and response to treatment of ITP. Sixty patients (30 boys and 30 girls) with ITP were enrolled into the study. We found that the age at the onset of ITP was from 1 month to 17 years (mean 7.0 ± 5.7 years), the platelet number was from 1 to 79 x 10(9)/L (mean 18.1 ± 19.0 x 10(9)/L) at the time of diagnosis and it increased from 17 to 395 x 10(9)/L (mean 134.4 ± 81.2 x 10(9)/L)(p < 0.05) after the first course of therapy. Forty seven patients required pharmacological treatment, the duration of the treatment was from 2 to 25 days (mean 6.1 ± 4.1 days). Relapses were observed in 27 (45%) of the patients. Active CMV infection was found in 19 patients (31.7%), EBV infection in 5 patients (8.3%), and both infections concomitantly in 1 patient (1.7%). The group of patients with CMV or EBV infection(n = 25) did not differ from the patients free of infection (n = 35) in regard to the age, number of platelets at onset, duration of treatment, number of platelets after treatment, number of relapses, and the interval between the onset and first relapse. In conclusion, active CMV or EBV infection is common in children with ITP. These infections do not seem to have an appreciable bearing on the clinical course and the response to treatment on children with ITP.

[Erythropoietin treatment of infants with anaemia in the first three months of life]. / Leczenie erytropoetyna niemowlat z niedokrwistoscia pierwszego kwartalu zycia.

UNLABELLED: Synthesis of recombinant human erythropoietin opened new possibilities for treatment of anaemia in infants. AIM: To assess the safety and effects of this treatment of anaemia in infants. MATERIAL AND METHODS: The study included 111 infants with anaemia aged between 3 and 10 weeks. Children were referred to the One Day Clinic of the Department of Paediatrics, Haematology and Oncology, Warsaw Medical University, by family doctors because of low haemoglobin concentration, in spite of iron supplementation. Patients were divided into two groups: group A - term infants and B - preterm infants. Both these groups were divided according to risk factors: serological incompatibility and infection at birth or just after birth. Recombinant human erythropoietin was given subcutaneously in doses of 500 IU/kg b. w./week. Therapy was ended when haemoglobin concentration reached 11 g/dl. RESULTS: Initial haemoglobin concentration in serum is the main factor which influence the length of recombinant human erythropoietin therapy of anaemia both in preterm and term infants. Serological incompatibility and infection at birth and just after birth lengthen the period of erythropoietin treatment of anaemia in both groups of patients. CONCLUSIONS: Recombinant human erythropoietin is an effective and fully safe drug in the treatment of anaemia in the first three months of life, both in preterm and term infants. Its high effectiveness is confirmed by comparative analysis of haematologic parameters in the first trimester of retrospective control group of infants without recombinant human erythropoietin therapy and term infants who had been treated with erythropoietin.

[Lymphoproliferative disorder as a complication after haematopoietic stem cell transplantation]. / Choroba limfoproliferacyjna jako powiklanie po przeszczepieniu komórek macierzystych szpiku.

Lymphoproliferative disorders (LPD) occur often in EBV-infected patients, especially in solid-organ and haematopoietic stem cell transplant recipients. The risk of developing LPD ranges from 1 to 25% and depends on the type of transplantation. We are presenting the case of a 9-year-old boy with acute myelogenous leukaemia in second remission, who developed LPD after matched unrelated donor bone marrow transplantation (MUD BMT) not identical in two loci. On day 50 after BMT the patient presented with fever and symptoms of paronychia. Two weeks later, bilateral cervical tenderness and adenopathy and hepatosplenomegaly developed. Bone marrow biopsy confirmed continuing remission. An extensive infection workup, including bacterial, mycotic and CMV infection yielded negative results. Basing on clinical picture and suspecting LPD, EBV-PCR was performed. The patient was found to have extremely high EBV DNA levels (4.905.152 genomes/mcg) in the peripheral blood. On days 64 and 73 after BMT, the patient received two doses of rituximab (MabThera) (375 mg/m(2)) After the first dose of rituximab EBV DNA copy numbers decreased to 707.723/mcg. However the patient's general condition was worsening; 71 days after BMT increasing aplasia and symptoms of venoocclusive disease (VOD) developed. The patient received two doses of defibrotide (Novarid). Despite of intensive therapy, progressive hepatic failure and increasing pulmonary oedema led to the patient's death, on day 96 after BMT.