Characteristics and treatment results of refractory and relapsed acute myeloid leukaemia in paediatric patients treated in Polish Paediatric Leukaemia/Lymphoma Study Group institutions according to the Protocol Acute Myeloid Leukaemia Berlin-Frankfurt-Munster 2012 and a review of novel treatment possibilities in paediatric acute myeloid leukaemia.

Introduction: This study aimed to present the clinical features and results of treatment of patients diagnosed with refractory or relapsed acute myeloid leukaemia (AML) in Polish Paediatric Leukaemia/Lymphoma Study Group (PPL/LSG) institutions, treated in accordance with the Protocol Acute Myeloid Leukaemia Berlin-Frankfurt-Munster 2012, as their first-line therapy. Material and methods: The outcome data of 10 patients with refractory AML (median age 9.5 years) and 30 with relapsed AML (median age 12 years) were analysed retrospectively. Re-induction was usually based on idarubicin, fludarabine, and cytarabine along with allogeneic haematopoietic stem cell transplant (allo-HSCT) in 5 patients with refractory AML and 7 relapsed AML children. Results: 37.5% (3/8) of refractory AML patients achieved second complete remission second complete remission (CRII). One of ten patients (1/10; 10%) was alive and stayed in complete remission for 34 months after the allo-HSCT. The probability of 3-year event-free survival (pEFS) in this group was 0.125 ±0.11. In the group of relapsed AML patients, the CRII was achieved in 9 patients (34%), and the probability of survival was: pEFS = 0.24 ±0.08; probability overall survival (pOS) = 0.34 ±0.09, with significantly better results achieved in patients who underwent allo-HSCT (pOS = 0.54 ±0.14 vs. 0.08 ±0.08, p < 0.0001). Conclusions: The prognosis of refractory AML and the first AML recurrence in children who were first-line treated in PPL/LSG centres according to Protocol Acute Myeloid Leukaemia Berlin-Frankfurt-Munster 2012 is poor. Failures of re-induction treatment particularly result from difficulties in achieving remission. Allogeneic HSCT improves prognosis in children with refractory and first recurrent AML, under the condition it is performed in complete remission. Novel therapeutic approaches are needed to increase the remission rate and improve the outcomes.

Clinical Characteristics and Treatment Outcomes of Myeloid Sarcoma in Children: The Experience of the Polish Pediatric Leukemia and Lymphoma Study Group.

Introduction: Myeloid sarcoma (MS) is an extramedullary malignant tumor composed of immature myeloid cells. It occurs in patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or chronic myeloid leukemia (CML). MS may coincide with disease diagnosis or precede bone marrow involvement by months or even years; it can also represent the extramedullary manifestation of a relapse (1, 2). Aim: The aim of this study is to describe clinical characteristics of children diagnosed with MS in Poland as well as to analyze diagnostic methods, treatment, and outcomes including overall survival (OS), relapse-free survival (RFS), and event-free survival (EFS). The study also attempted to identify factors determining treatment outcomes. Patients: The study group comprised 43 patients (F=18, M=25) aged 0-18 years (median age, 10.0 years; mean age, 8.8 years) diagnosed with MS based on tumor biopsy and immunohistochemistry or identification of underlying bone marrow disease and extramedullary tumor according to imaging findings. Methods: The clinical data and diagnostic and therapeutic methods used in the study group were analyzed. A statistical analysis of the treatment outcomes was conducted with STATISTICA v. 13 (StatSoft, Inc., Tulsa, OK, USA) and analysis of survival curves was conducted with MedCalc 11.5.1 (MedCalc Software, Ostend, Belgium). Statistical significance was considered at p<0.05. Results: In the study group, MS was most frequently accompanied by AML. The most common site of involvement was skin, followed by orbital region. Skin manifestation of MS was more common in the age group <10 years. The most frequent genetic abnormality was the t(8;21)(q22;q22) translocation. The 5-year OS probability (pOS), 5-year RFS probability (pRFS), and 5-year EFS probability (pEFS) were 0.67 ± 0.08, 0.79 ± 0.07, and 0.65 ± 0.08, respectively. In patients with isolated MS and those with concurrent bone marrow involvement by AML/MDS, pOS values were 0.56 ± 0.12 and 0.84 ± 0.09 (p=0.0251), respectively, and pEFS values were 0.56 ± 0.12 and 0.82 ± 0.08 (p=0.0247), respectively. In patients with and without the t(8;21)(q22;q22) translocation, pEFS values were 0.90 ± 0.09 and 0.51 ± 0.14 (p=0.0490), respectively. Conclusions: MS is a disease with a highly variable clinical course. Worse treatment outcomes were observed in patients with isolated MS compared to those with concurrent bone marrow involvement by AML/MDS. Patients with the t(8;21)(q22;q22) translocation were found to have significantly higher pEFS. MS location, age group, chemotherapy regimen, surgery, and/or radiotherapy did not have a significant influence on treatment outcomes. Further exploration of prognostic factors in children with MS is indicated.

Prospective analysis of BKV hemorrhagic cystitis in children and adolescents undergoing hematopoietic cell transplantation.

BK virus is one of the most common causes of hemorrhagic cystitis (HC) in children undergoing hematopoietic cell transplantation (HCT). Viruses can be found in urine and serum samples of immunocompromised patients. Malignant diseases, age, cell source, day of granulocyte reconstitution, conditioning regimen, or use of total body irradiation may play an important role in BKV epidemiology, development of hemorrhagic cystitis course, and outcome. The aim of this study was to evaluate the incidence, clinical course, and risk factors for BKV-HC in children undergoing HCT. A total number of 133 patients who were prospectively tested for BKV colonization/infection were enrolled into this multicenter analysis. Episodes of BKV-HC occurred in 36/133 (27%) enrolled subjects. In a univariate analysis for BKV-HC incidence, the following factors were significant: age >5 years, peripheral blood transplantation, matched unrelated donor (MUD) transplantation, busulfan-cyclophosphamide-melphalan conditioning regimen, and acute myeloblastic leukemia (AML) diagnosis. Presence of acute graft-versus-host disease (aGVHD) in liver and gut GVHD was a significant risk factor of BKV-HC. No BKV-attributed deaths were reported. In multivariate analysis, the incidence of HC was significantly higher in patients with AML, age >5 years, MUD transplants, and children with GVHD. HC is a frequent complication after HCT among children causes prolonged hospitalization but rarely contributes to death. We identified risk factors of BKV-HC development in children, with focus on aGVHD: we concluded that excessive immune reaction connected with GVHD and immunosuppression drugs might play a pivotal role in the development of BKV-HC.

Prevalence, Epidemiology, Etiology, and Sensitivity of Invasive Bacterial Infections in Pediatric Patients Undergoing Oncological Treatment: A Multicenter Nationwide Study.

Background: Infectious complications (IC) caused by bacterial strains often impede anticancer therapy. The study aimed to retrospectively analyze bacterial IC that could help predict the risk and optimize the empirical treatment for bacterial infections in pediatric cancer patients. Patients and Methods: Over a 72-month period, all-in 5,599 children with cancer: 2,441 patients with hematological malignancy (HM including acute leukemias, Hodgkin and non-Hodgkin lymphomas [NHLs], and Langerhans cell histiocytosis) and 3,158 with solid tumors (STs including central nervous system tumors, neuroblastoma, Wilms' tumor, soft tissue sarcoma, germ cell tumors, Ewing sarcoma, osteosarcoma, hepatoblastoma, and others) were enrolled into the study. Episodes of bacterial infectious complications (EBICs) confirmed by microbiological findings were reported by each hospital and analyzed centrally. Results: At least 1 EBIC was diagnosed in 2,155 (36.8%) children (1,281 [59.4%] with HM and 874 [40.6%] with ST; p < 0.001). All-in 4,860 EBICs were diagnosed including 62.2% episodes in children with HM and 37.8% in children with ST (p < 0.001). Having analyzed the source of infections, blood stream infections predominated, apart from NHL patients in whom the most common type was gut infections. The profile of bacteria strains was different in HM and ST groups (p < 0.001). However, in both groups the most common Gram-negative pathogen was Enterobacteriaceae, with the rate being higher in the HM group. Among Gram-negative strains low susceptibility to ceftazidime, whereas among Enterococcus spp. low susceptibility to vancomycin was noticed. The rate of multidrug-resistant (MDR) pathogens was high, especially for Gram negatives (47.7% vs. 23.9%; p < 0.001). The survival after infections was comparable for HM and ST patients (p = 0.215). Conclusions: The risk of bacterial IC in HM patients was higher than in the ST group. The high rate of MDR strains was detected in pediatric cancer patients, especially in those with HM.

High Frequency of Fusion Gene Transcript Resulting From t(10;11)(p12;q23) Translocation in Pediatric Acute Myeloid Leukemia in Poland.

11q23/MLL rearrangements are frequently detected in pediatric acute myeloid leukemia. The analysis of their clinical significance is difficult because of the multitude of translocation fusion partners and their low frequency. The presence of t(10;11)(p12;q23) translocation was previously identified in pediatric acute myelogenous leukemia (AML). It is considered as the second most common translocation detected in pediatric 11q23/MLL-rearranged (present KMT2A) AML, after t(9;11)(p22;q23). The presence of the above translocation was previously identified as an unfavorable prognostic factor. Since June 2015, the Polish Pediatric Leukemia/Lymphoma Study Group has applied the therapeutic protocol requiring extensive diagnostics of genetic changes in pediatric AML. Until November 2019, molecular genetic studies were performed in 195 children with diagnosed AML to identify carriers of fusion gene transcripts for 28 most common chromosomal translocations in acute leukemia. The fusion gene transcript for translocation t(10;11)(p12;q23) involving MLL gene was detected with unexpectedly high frequency (8.9%) in our research. It was the highest frequency of all detected MLL rearrangements, as well as other detected fusion gene transcripts from chromosomal aberrations characteristic for AML. It seems that chromosomal aberration between chromosomes 10 and 11 can be relatively frequent in some populations. Paying attention to this fact and ensuring proper genetic diagnosis seem to be important for appropriate allocation of patients to risk groups of pediatric AML treatment protocols.

Retrospective Analysis of the Treatment Outcome in Myeloid Leukemia of Down Syndrome in Polish Pediatric Leukemia and Lymphoma Study Group From 2005 to 2019.

Background: Children with Down syndrome (DS) have increased risk of myeloid leukemia (ML), but specific treatment protocols ensure excellent outcome. This study was a retrospective analysis of the treatment results and genetic characteristics of ML of DS (ML-DS) in Poland from 2005 to 2019. Methods: All 54 patients with ML-DS registered in the Polish Pediatric Leukemia and Lymphoma Study Group in analyzed period were enrolled to the study. There were 34 children treated with Acute Myeloid Leukemia-Berlin-Frankfurt-Munster 2004 Interim Protocol (group I) and 20 patients treated with ML-DS 2006 Protocol (group II). In the first protocol, there was reduction of the antracyclines doses and intrathecal treatment for ML-DS compared to non-DS patients. In the second protocol, further reduction of the treatment was introduced (omission of etoposide in the last cycle, no maintenance therapy). Results: Probabilities of 5-year overall survival (OS), event-free survival (EFS), and relapse-free survival in the whole analyzed group were 0.85 ± 0.05, 0.83 ± 0.05, and 0.97 ± 0.03, respectively. No significant differences were found between two protocols in the terms of OS and EFS (0.79 ± 0.07 vs. 0.95 ± 0.05, p = 0.14, and 0.76 ± 0.07 vs. 0.95 ± 0.05, p = 0.12, respectively). All deaths were caused by the treatment-related toxicities. Reduction of the treatment-related mortality was noticed (20% in group I and 5% in group II). The only one relapse in the whole cohort occurred in the patient from group I, older than 4 years, without GATA1 gene mutation. He was treated successfully with IdaFLA cycle followed by hematopoietic stem cell transplantation from matched sibling donor. No significant prognostic factor was found in the study group probably due to low number of patients in the subgroups. Conclusions: The study confirms that the reduced intensity protocols are very effective in ML-DS patients. The only cause of deaths was toxicities; however, systematic decrease of the treatment-related mortality was noticed.

Correction: Long-term outcome after allogeneic hematopoietic stem cell transplantation for Shwachman-Diamond syndrome: a retrospective analysis and a review of the literature by the Severe Aplastic Anemia Working Party of the European Society for Blood and Marrow Transplantation (SAAWP-EBMT).

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Treatment Outcome and the Genetic Characteristics of Acute Promyelocytic Leukemia in Children in Poland From 2005 to 2018.

Background: The aim of the study was to analyze the treatment outcome and genetic characteristics of acute promyelocytic leukemia (APL) in children in Poland from 2005 to 2018. Methods: All 41 patients diagnosed with APL in Poland during the analysis period were eligible for the study. In period I (2005-2015), 33 patients were treated with chemotherapy and all-trans retinoic acid (ATRA), and in period II (2015-2018), 3 patients (high risk) received induction chemotherapy with ATRA and arsenic trioxide (ATO), and 5 patients (standard risk) received ATRA and ATO without chemotherapy. Results: Probability of 5-years overall survival (OS), event-free survival (EFS), and relapse-free survival (RFS) was 0.819 ± 0.069, 0.831 ± 0.063, and 0.961 ± 0.037, respectively, in the whole cohort. Four (11%) early deaths were observed. One patient died of severe infection in the course of disease progression. Relapse occurred in one patient, who died finally because of disease progression. All events occurred in the patients from period I. Variant APL was identified in one patient (successfully treated with chemotherapy with ATRA) and complex translocation in one patient (the only patient with relapse). Additional chromosomal aberrations were found in 26% of patients and FLT3-ITD mutation was detected in 44% of patients; none of those changes influenced clinical outcome. Conclusion: Treatment outcome in the analyzed group is similar to the results reported by other study groups. The main cause of death was coagulation disorders in the early stage of disease. Early, accurate diagnosis followed by specific treatment enables the reduction in the number of early deaths.

Myeloablative conditioning for allo-HSCT in pediatric ALL: FTBI or chemotherapy?-A multicenter EBMT-PDWP study.

Although most children with acute lymphoblastic leukemia (ALL) receive fractionated total body irradiation (FTBI) as myeloablative conditioning (MAC) for allogeneic hematopoietic stem cell transplantation (allo-HSCT), it is an important matter of debate if chemotherapy can effectively replace FTBI. To compare outcomes after FTBI versus chemotherapy-based conditioning (CC), we performed a retrospective EBMT registry study. Children aged 2-18 years after MAC for first allo-HSCT of bone marrow (BM) or peripheral blood stem cells (PBSC) from matched-related (MRD) or unrelated donors (UD) in first (CR1) or second remission (CR2) between 2000 and 2012 were included. Propensity score weighting was used to control pretreatment imbalances of the observed variables. 3.054 patients were analyzed. CR1 (1.498): median follow-up (FU) after FTBI (1.285) and CC (213) was 6.8 and 6.1 years. Survivals were not significantly different. CR2 (1.556): median FU after FTBI (1.345) and CC (211) was 6.2 years. Outcomes after FTBI were superior as compared with CC with regard to overall survival (OS), leukemia-free survival (LFS), relapse incidence (RI), and nonrelapse mortality (NRM). However, we must emphasize the preliminary character of the results of this retrospective "real-world-practice" study. These findings will be prospectively assessed in the ALL SCTped 2012 FORUM trial.

Long-term outcome after allogeneic hematopoietic stem cell transplantation for Shwachman-Diamond syndrome: a retrospective analysis and a review of the literature by the Severe Aplastic Anemia Working Party of the European Society for Blood and Marrow Transplantation (SAAWP-EBMT).

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative procedure in patients with Shwachman-Diamond syndrome (SDS) with bone marrow abnormalities. The results of 74 patients with SDS (6 acute myeloid leukemia, 7 myelodysplastic syndrome, and 61 bone marrow failure) treated with HSCT between 1988 and 2016 are reported. The donor source was: 24% sibling, 8% parent, and 68% unrelated donor. The stem cell source was: 70% bone marrow, 19% peripheral blood stem cells, and 11% cord blood. The conditioning regimen was myeloablative in 54% and reduced intensity in 46%. Neutrophil engraftment was achieved in 84% of patients after a median time of 17.5 days. Graft failure occurred in 15% of HSCTs. Grades I-IV acute and chronic GVHD were observed in 55% and 20% of patients, respectively. After a median follow-up of 7.3 years (95% CI 4.8-10.2), 28 patients died for progression/relapse (7) or toxicity (21). The 5-year overall survival and nonrelapse mortality were 63.3% (95% CI 50.8-73.4) and 19.8% (95% CI 10.8-30.8), respectively. In conclusion, this is the largest series so far reported and confirms that HSCT is a suitable option for patients with SDS. Further efforts are needed to lower transplant-related toxicity and reduce graft failure.

Infectious complications after hematopoietic stem cell transplantation for primary immunodeficiency in children: A multicenter nationwide study.

PURPOSE: The aim of this nationwide study was to evaluate the characteristics of bacterial infections (BI), invasive fungal disease (IFD), and viral infections (VI) in pediatric patients with PID after allogeneic hematopoietic stem cell transplantation (allo-HSCT). PATIENTS AND METHODS: In total, 114 HSCT recipients were enrolled into the study. At least one infectious complication (IC) was diagnosed in 60 (52.6%) patients aged 0.1-17.7 years, that is, 59.5% with SCID and 49.4% with non-SCID. RESULTS: Among 60 HSCT recipients diagnosed with at least one IC, 188 episodes of infectious complications (EIC) were recorded, that is, 46.8% of BI, 41.5% of VI, and 11.7% of proven/probable IFD. According to PID and HSCT donor type, the incidence of EIC was comparable (P = .679). The localization of infections differed significantly due to PID type (P = .002). After each HSCT donor type, the most common site of infection was GI. Overall, BI caused by Gram-positive strains (59.1%) were prevalent, especially Staphylococcaceae. The multidrug-resistant (MDR) pathogens were diagnosed in 52.3%, especially ESBL + Enterobacteriaceae. The profile of VI was comparable for SCID and non-SCID patients (P = .839). The incidence of IFD was comparable for each PID and HSCT donor type. Survival after infection was 91.5% and was comparable for PID and HSCT donor type. CONCLUSIONS: The rate of patients diagnosed with IC among pediatric PID-HSCT recipients did not depend on PID type, but rather on HSCT donor type. The localization of IC depended on PID and HSCT donor type. Within bacterial infections, predominated Gram-positive strains and the MDR pathogens were responsible for more than half of EIC.

Mixed phenotype acute leukemia: Biological profile, clinical characteristic and treatment outcomes: Report of the population-based study.

OBJECTIVES: The aim of this population-based, retrospective study was to analyze biological and clinical features and treatment results in children diagnosed with MPAL in all Polish pediatric oncology centers between 2007 and 2018. METHODS: Among 2893 children and adolescents diagnosed and treated for acute leukemia, 39 (1.35%) patients fulfilled the WHO criteria of MPAL. The T/myeloid phenotype was most prevalent. RESULTS: Cytogenetics findings were seen in 2 (5.1%), while chromosomal abnormalities were found in 14 (35.9%) patients. Thirty-two patients achieved CR-1, including 23 (92.0%) treated with ALL-directed chemotherapy and 9 (64.3%) treated with AML-type induction regimens. Within these patients, 4 (12.5%) died due to treatment-related complications and 11 (34.4%) relapsed. Nineteen (63.3%) patients underwent allo-HSCT in CR-1 and 14 (73.7%) of them have been in CR-1. In total, 17 (43.6%) patients remain in CR-1 for 1-12 years, including 14 (58.3%) with T/myeloid MPAL. The 5-year pOS and pEFS were 51.8% and 44.2%, respectively. The overall survival for ALL-directed therapy was significantly better than the one for AML-type chemotherapy (P = .001). It was also better for patients who underwent HSCT in CR-1 (P = .001). CONCLUSIONS: The prognosis of MPAL is unsatisfactory, but initial treatment with ALL-directed chemotherapy consolidated with allo-HSCT improves the outcomes in MPAL.

The influence of different intensity of treatment on hormonal markers of gonadal function in acute lymphoblastic leukemia survivors.

Anti-cancer treatment in children can deteriorate gonadal function and affect future fertility. We analyzed the hormonal markers of gonadal function in adolescent leukemia survivors, treated in childhood with different levels of aggressiveness. We analyzed hormone levels in 69 adolescents and young adults, leukemia survivors stratified into standard (SR), intermediate (IR), and high (HR) risk groups, and in 80 healthy controls (38 men) at a similar age. We assessed follicular stimulating hormone (FSH), luteinizing hormone (LH), and inhibin B in the whole group, testosterone in males, and E2 and anti-Müllerian hormone (AMH) in females. Males classified into HR group presented, in comparison to control, higher levels of FSH, LH, lower inhibin B, and normal testosterone, whereas in SR and IR group, the hormonal values were comparable to the control. In females, in all risk groups, the levels of FSH, LH, E2, and inhibin B were comparable with the control, but the mean AMH levels were slightly lowered. We did not observe the effect of prophylactic cranial irradiation (12 or 18 Gy) or the time of treatment (before vs. during puberty) on hormone levels. In females, a positive correlation was found between the time interval after the end of treatment and AMH levels. Male leukemia survivors having undergone more intensive chemotherapy show the symptoms of disturbed spermatogenesis and need to be followed-up in the future. Women, irrespective of the risk group, can develop the signs of preterm ovarian insufficiency. They should be informed about the impact of the treatment on gonadal function.

Infections in children with acute myeloid leukemia: increased mortality in relapsed/refractory patients.

The aim of this nationwide study was to describe the epidemiology and profile of bacterial infections (BI), invasive fungal disease (IFD) and viral infections (VI) in patients with de novo and relapsed/refractory (rel/ref) acute myeloid leukemia (AML). Within the studied group of 250 children with primary AML, at least one infectious complication (IC) was diagnosed in 76.0% (n = 190) children including 85.1% (n = 504) episodes of BI, 8.3% (n = 49) - IFD and 6.6% (n = 39) - VI. Among 61 patients with rel/ref AML, at least one IC was found in 67.2% (n = 41) of children including 78.8% (n = 78) of BI, 14.1% (n = 14) of IFD and 7.1% (n = 7) of VI. In all AML patients, within BI Gram-negative strains were predominant. Half of these strains were multi-drug resistant. Characteristics of IFD and VI were comparable for de novo and rel/ref AML. The infection-related mortality was significantly higher, while survival from infection was significantly lower in patients with rel/ref disease.

Endothelial Function in Children with Acute Lymphoblastic Leukemia (ALL) May Reflect the Clinical Outcome.

Endothelial dysfunction is a common feature of early complications of hemato-oncologic therapy. The aim of our study was to assess the profile of endothelial function at diagnosis time, then during initial treatment phase of acute lymphoblastic leukemia (ALL), and to verify the presence of its correlation with early clinical outcome (ECO). 28 ALL children and 18 healthy age-matched control ones were recruited. Study group was examined at baseline and at 33rd and 78th day of treatment. At each protocol step the endothelial function was assessed by measurement of sP-selectin (CD62-P), PAI-1(serpinE1), sE-selectin (CD62E), sICAM-1(sCD54), sVCAM-1(sCD106), and VEGF concentrations. Higher baseline sICAM-1 and sVCAM-1 levels and lower sP-selectin and VEGF were observed in children with ALL. sICAM-1, sVCAM-1, and sE-selectin levels were decreasing following the treatment with protocol I. Higher sE-selectin and lower baseline sICAM-1 levels were observed in children treated unsuccessfully. Lower PAI-1 levels were observed in children who survived. Higher baseline sE-selectin levels and lower sICAM-1 and VEGF were observed in children treated unsuccessfully. A decrease in sE-selectin and lower PAI-1 at the 78th day of therapy were associated with better ECO. High baseline VEGF and sE-selectin levels, significant increase in PAI-1, and low initial sICAM-1 levels are prognostics for poorer prognosis in the ALL children.

Development and current use of in hematopoietic stem cell transplantation in children and adolescents in Poland: Report of the Polish pediatric study group for hematopoietic stem cell transplantation of the Polish society for pediatric oncology and hematology.

The purpose of the survey was to evaluate the development and current use of hematopoietic stem cell transplantation (HSCT) in Poland between 1989-2016. The data for analysis (indication, number of performed HSCT, HSCT type, donor type, and stem cell source, year) have been collected annually using a standardized form. In Poland, between 1989-2016, the number of pediatric transplant beds grew from one to 40 and number and rate of transplants increased annually from 1/year (0.8/10 million) to 186/year (248/10 million). During the analyzed time period 2506 HSCTs were performed, including 1718 (68.6%) allogeneic transplants (allo-HSCT) with142 in 2016 and 788 (31.4%) autologous transplants (auto-HSCT) with 44 in 2016. Among 1718 allo-HSCT, 74% were performed for malignancy (ALL 47.2%, AML 26.2%, MDS 10.8%, CML 8.1%, NHL/HD 6.1%, others 2.5%), and 26% for non-malignant disorders (SAA 41%, congenital immunodeficiencies 35.4%, hereditary bone marrow failure 16%, metabolic disorders 7%). Among 788 auto-HSCTs, 30.8% were done for hematological malignancy (NHL 41.2%, AML 23.9%, HD 17.7%, ALL 15.6%, other 1.5%), while the remaining 69.2% for solid tumors (neuroblastoma 59.8%, Ewing's sarcoma 20.4%, other 19.8%). In Poland, between 1989-2016, the infrastructure indispensable to perform HSCT in every child with indication for this therapeutic procedure was created, and HSCT became an important part of pediatric treatment, especially in pediatric oncology, hematology, and in primary immunodeficiencies.

A risk factor analysis of outcomes after unrelated cord blood transplantation for children with Wiskott-Aldrich syndrome.

Wiskott-Aldrich syndrome is a severe X-linked recessive immune deficiency disorder. A scoring system of Wiskott-Aldrich syndrome severity (0.5-5) distinguishes two phenotypes: X-linked thrombocytopenia and classic Wiskott-Aldrich syndrome. Hematopoietic cell transplantation is curative for Wiskott-Aldrich syndrome; however, the use of unrelated umbilical cord blood transplantation has seldom been described. We analyzed umbilical cord blood transplantation outcomes for 90 patients. The median age at umbilical cord blood transplantation was 1.5 years. Patients were classified according to clinical scores [2 (23%), 3 (30%), 4 (23%) and 5 (19%)]. Most patients underwent HLA-mismatched umbilical cord blood transplantation and myeloablative conditioning with anti-thymocyte globulin. The cumulative incidence of neutrophil recovery at day 60 was 89% and that of grade II-IV acute graft-versus-host disease at day 100 was 38%. The use of methotrexate for graft-versus-host disease prophylaxis delayed engraftment (P=0.02), but decreased acute graft-versus-host disease (P=0.03). At 5 years, overall survival and event-free survival rates were 75% and 70%, respectively. The estimated 5-year event-free survival rates were 83%, 73% and 55% for patients with a clinical score of 2, 4-5 and 3, respectively. In multivariate analysis, age <2 years at the time of the umbilical cord blood transplant and a clinical phenotype of X-linked thrombocytopenia were associated with improved event-free survival. Overall survival tended to be better in patients transplanted after 2007 (P=0.09). In conclusion, umbilical cord blood transplantation is a good alternative option for young children with Wiskott-Aldrich syndrome lacking an HLA identical stem cell donor.

Elevated plasma ADMA contributes to development of endothelial dysfunction in children with acute lymphoblastic leukemia.

BACKGROUND: Childhood acute lymphoblastic leukemia (ALL) survivors are at higher cardiovascular risk than the general population, which may result from anthracycline-related endothelial dysfunction (ED). However, a few studies indirectly show that ED may appear in ALL children before treatment begins. Hence, in this study we intended to verify the hypothesis that ED is part of the ALL phenotype. PATIENTS/METHODS: Twenty-eight ALL children and 14 healthy age-matched control children were recruited. The study group was examined at baseline, then at the 33rd and 78th day of treatment. At each step of the protocol endothelial vasodilative function was assessed by a laser Doppler flowmeter, which was followed by blood collecting for subsequent analyses. RESULTS: Compared to controls, the study group at baseline was characterized by significantly lower endothelial vasodilative responsiveness, accompanied by elevated asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) concentrations, which were correlated with lactate dehydrogenase (LDH) and aspartate transaminase (AST). Initial ALL treatment restored endothelial function, which followed changes in ADMA and LDH concentrations. DISCUSSION: This is the first demonstration that functionally assessed ED is present in ALL children at the diagnosis and results from elevated ADMA and parallel inflammatory ED.

Unrelated alternative donor transplantation for severe acquired aplastic anemia: a study from the French Society of Bone Marrow Transplantation and Cell Therapies and the EBMT Severe Aplastic Anemia Working Party.

Unrelated allogeneic transplantation for severe aplastic anemia is a treatment option after immunosuppressive treatment failure in the absence of a matched sibling donor. Age, delay between disease diagnosis and transplantation, and HLA matching are the key factors in transplantation decisions, but their combined impact on patient outcomes remains unclear. Using the French Society of Bone Marrow Transplantation and Cell Therapies registry, we analyzed all consecutive patients (n=139) who underwent a first allogeneic transplantation for idiopathic severe aplastic anemia from an unrelated donor between 2000 and 2012. In an adjusted multivariate model, age over 30 years (Hazard Ratio=2.39; P=0.011), time from diagnosis to transplantation over 12 months (Hazard Ratio=2.18; P=0.027) and the use of a 9/10 mismatched unrelated donor (Hazard Ratio=2.14; P=0.036) were independent risk factors that significantly worsened overall survival. Accordingly, we built a predictive score using these three parameters, considering patients at low (zero or one risk factors, n=94) or high (two or three risk factors, n=45) risk. High-risk patients had significantly shorter survival (Hazard Ratio=3.04; P<0.001). The score was then confirmed on an independent cohort from the European Group for Blood and Marrow Transplantation database of 296 patients, with shorter survival in patients with at least 2 risk factors (Hazard Ratio=2.13; P=0.005) In conclusion, a simple score using age, transplantation timing and HLA matching would appear useful to help physicians in the daily care of patients with severe aplastic anemia.