Publications by authors named "Jacek Wachowiak"

119 Publications

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

Sci Rep 2020 11 19;10(1):20168. Epub 2020 Nov 19.

Department of Pediatric Hematology, Oncology and Transplantology, Medical University of Lublin, Antoni Gębala Street 6, 20-093, Lublin, Poland.

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.
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http://dx.doi.org/10.1038/s41598-020-75860-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678856PMC
November 2020

Psychosocial Late Effects in Adolescent and Young Adult Survivors of Childhood Cancer Diagnosed with Leukemia, Lymphoma, and Central Nervous System Tumor.

J Adolesc Young Adult Oncol 2020 Aug 27. Epub 2020 Aug 27.

Department of Pediatric Oncology, Hematology and Transplantology, and Poznan University of Medical Sciences, Poznan, Poland.

The prevalence of psychosocial late effects and quality of life in adolescent and young adult (AYA)-aged survivors of pediatric cancer have been studied. The study was conducted in AYA survivors who had been diagnosed with leukemia, lymphoma, or brain tumor, had completed treatment at least 1 year before the study, and were 15-39 years old at study enrollment. The control group consisted of healthy volunteers. A questionnaire comprised a demographic form, eight questions concerning mental health and the disease, and survey The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30. Controls received a questionnaire without questions concerning an illness. Most of survivors believed that cancer treatment might have a serious influence on their health. Survivors significantly more frequently declared using drugs: neuroleptics, tranquilizers, and antidepressants than controls. Survivors of leukemia demonstrated significantly more problems in cognitive functioning than lymphoma survivors. Females were significantly more disabled in emotional functioning than males. Young adults more often reported dysfunction in emotional functioning compared to adolescents. Survivors who were assessed ≥10 years since therapy reported significantly more disadvantage in social functioning than those assessed <10 years since treatment completion. Survivors reported significantly more disadvantages in social functioning than controls. Allogeneic hematopoietic stem cell transplantation survivors more often suffered cognitive limitations. Irradiated survivors more often attended psychological therapy. Survivors of pediatric cancer are vulnerable to consequences of oncological treatment, making their quality life significantly worse in comparison with healthy controls. They need to be monitored, supported, and educated.
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http://dx.doi.org/10.1089/jayao.2020.0086DOI Listing
August 2020

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

Front Pediatr 2020 10;8:278. Epub 2020 Jul 10.

Department of Pediatric Oncology and Hematology, Faculty of Medicine, Jagiellonian University Medical College, Kraków, Poland.

11q23/ 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/-rearranged (present ) 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 gene was detected with unexpectedly high frequency (8.9%) in our research. It was the highest frequency of all detected 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.
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http://dx.doi.org/10.3389/fped.2020.00278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366384PMC
July 2020

The impact of donor type on the outcome of pediatric patients with very high risk acute lymphoblastic leukemia. A study of the ALL SCT 2003 BFM-SG and 2007-BFM-International SG.

Bone Marrow Transplant 2021 Jan 4;56(1):257-266. Epub 2020 Aug 4.

St Anna Children's Hospital, Universitätsklinik für Kinder- und Jugendheilkunde, Medizinische Universität Wien, Vienna, Austria.

Allogeneic HSCT represents the only potentially curative treatment for very high risk (VHR) ALL. Two consecutive international prospective studies, ALL-SCT-(I)BFM 2003 and 2007 were conducted in 1150 pediatric patients. 569 presented with VHR disease leading to any kind of HSCT. All patients >2 year old were transplanted after TBI-based MAC. The median follow-up was 5 years. 463 patients were transplanted from matched donor (MD) and 106 from mismatched donor (MMD). 214 were in CR1. Stem cell source was unmanipulated BM for 330 patients, unmanipulated PBSC for 135, ex vivo T-cell depleted PBSC for 62 and cord-blood for 26. There were more advanced disease, more ex vivo T-cell depletion, and more chemotherapy based conditioning regimen for patients transplanted from MMD as compared to those transplanted from MSD or MD. Median follow up (reversed Kaplan Meier estimator) was 4.99 years, median follow up of survivals was 4.88, range (0.01-11.72) years. The 4-year CI of extensive cGvHD was 13 ± 2% and 17 ± 4% (p = NS) for the patients transplanted from MD and MMD, respectively. 4-year EFS was statistically better for patients transplanted from MD (60 ± 2% vs. 42 ± 5%, p < 0.001) for the whole cohort. This difference does not exist if considering separately patients treated in the most recent study. There was no difference in 4-year CI of relapse. The 4-year NRM was lower for patients transplanted from MD (9 ± 1% vs. 23 ± 4%, p < 0.001). In multivariate analysis, donor-type appears as a negative risk-factor for OS, EFS, and NRM. This paper demonstrates the impact of donor type on overall results of allogeneic stem cell transplantation for very-high risk pediatric acute lymphoblastic leukemia with worse results when using MMD stem cell source.
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http://dx.doi.org/10.1038/s41409-020-01014-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796856PMC
January 2021

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

Front Pediatr 2020 19;8:277. Epub 2020 Jun 19.

Department of Pediatric Oncology and Hematology, Institute of Pediatrics, Jagiellonian University Medical College, Kraków, Poland.

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. 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). 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, = 0.14, and 0.76 ± 0.07 vs. 0.95 ± 0.05, = 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 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. 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.
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http://dx.doi.org/10.3389/fped.2020.00277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317010PMC
June 2020

First case of convalescent plasma transfusion in a child with COVID-19-associated severe aplastic anemia.

Transfus Apher Sci 2020 Oct 1;59(5):102866. Epub 2020 Jul 1.

Department of Infectious Diseases and Child Neurology, Poznan University of Medical Sciences, Szpitalna 27/33, 60-572 Poznań, Poland.

We present the case of a six-year-old girl with severe COVID-19, in whom SARS-CoV-2 was successfully eliminated after convalescent plasma transfusion. Children show a variable clinical course of COVID-19, from asymptomatic to critical. In our patient, we diagnosed COVID-19-associated aplastic anemia with severe pancytopenia. The correlation between SARS-CoV-2 infection with aplastic anemia remains unclear. At the beginning of the disease, we used antiviral drugs and immune modulators as therapy but without any positive results. After providing a transfusion of convalescent plasma, the elimination of SARS-CoV-2 was observed. We did not observe any adverse events of this treatment. The girl still has a diagnosis of aplastic anemia and requires specialist therapy.
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http://dx.doi.org/10.1016/j.transci.2020.102866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328608PMC
October 2020

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

Microb Drug Resist 2021 Jan 20;27(1):53-63. Epub 2020 May 20.

Department of Pediatric Hematology and Oncology and Collegium Medicum, Nicolaus Copernicus University Torun, Bydgoszcz, Poland.

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. 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. At least 1 EBIC was diagnosed in 2,155 (36.8%) children (1,281 [59.4%] with HM and 874 [40.6%] with ST;  < 0.001). All-in 4,860 EBICs were diagnosed including 62.2% episodes in children with HM and 37.8% in children with ST ( < 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 ( < 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 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%;  < 0.001). The survival after infections was comparable for HM and ST patients ( = 0.215). 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.
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http://dx.doi.org/10.1089/mdr.2019.0393DOI Listing
January 2021

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

Front Pediatr 2020 20;8:86. Epub 2020 Mar 20.

Department of Pediatric Oncology and Hematology, Institute of Pediatrics, Jagiellonian University Medical College, Krakow, Poland.

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. 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. 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. 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.
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http://dx.doi.org/10.3389/fped.2020.00086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7100382PMC
March 2020

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

Eur J Haematol 2020 Jul 17;105(1):85-93. Epub 2020 Apr 17.

Department of Pediatric Oncology, Hematology and Transplantology, Poznan University of Medical Sciences, Poznan, Poland.

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.
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http://dx.doi.org/10.1111/ejh.13413DOI Listing
July 2020

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

Bone Marrow Transplant 2020 08 17;55(8):1540-1551. Epub 2020 Mar 17.

Division for Stem Cell Transplantation and Immunology, Department for Children and Adolescents, University Hospital, Goethe University Frankfurt, Frankfurt, Germany.

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.
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http://dx.doi.org/10.1038/s41409-020-0854-0DOI Listing
August 2020

Long-term brain status and cognitive impairment in children treated for high-risk acute lymphoblastic leukemia with and without allogeneic hematopoietic stem cell transplantation: A single-center study.

Pediatr Blood Cancer 2020 06 20;67(6):e28224. Epub 2020 Mar 20.

Department of Pediatric Oncology, Hematology and Transplantology, Poznan University of Medical Sciences, Poznań, Poland.

Aim: The aim of the study was to assess long-term consequences of central nervous system (CNS) prophylaxis in patients with high-risk ALL (HR-ALL) treated according to ALL IC-BFM 2002 and to compare observed abnormalities in patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) with those who received only prophylactic CNS irradiation (12 Gy) and with control group.

Patients And Methods: We studied 29 patients with HR-ALL in CR1 after treatment according to protocol ALL IC-BFM 2002 (14 with allo-HSCT conditioned with fractionated total body irradiation [FTBI] and 15 without HSCT) and 16 children with newly diagnosed ALL (control group). The median time from therapy completion to evaluation was 5 years. To assess brain status, volumetric T1-weighted sequences of magnetic resonance imaging were used. Neuropsychological assessment based on battery neuropsychological tests.

Results: Transplanted patients had significantly lower volumes of white and gray matter (P = .048 and P < .001) and also of subcortical structures, including the thalamus (P < .001), the hippocampus (P = .007), the putamen (P = .011), the globus pallidus (P = .001), and the accumbens (P < .001). In addition, these patients had generally lower cognitive performance, especially in vocabulary (P = .011), visuospatial ability (P = .047), executive functions and attention (P = .034; P = .002; P = .048), and processing speed (P = .049 and P = .037). The thalamus volume is correlated with neuropsychological performance in verbal functions (P < .001), executive functions (P < .001 and P = .024), and processing speed (P < .001).

Conclusions: In pediatric patients treated for ALL, FTBI-based preparative regimen preceding allo-HSCT causes reduction of subcortical structure volumes and decline in cognitive performance. The observed long-term structural and functional CNS sequelae are significantly more pronounced in transplanted HR-ALL patients than in those treated with prophylactic CNS- radiotherapy only.
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http://dx.doi.org/10.1002/pbc.28224DOI Listing
June 2020

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

Pediatr Allergy Immunol 2020 07 6;31(5):537-543. Epub 2020 Apr 6.

Department of Pediatric Hematology and Oncology, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland.

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.
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http://dx.doi.org/10.1111/pai.13239DOI Listing
July 2020

Pediatric acute graft-versus-host disease prophylaxis and treatment: surveyed real-life approach reveals dissimilarities compared to published recommendations.

Transpl Int 2020 Jul 2;33(7):762-772. Epub 2020 Apr 2.

Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, University of Hospital Regensburg, Regensburg, Germany.

Pediatric allogeneic hematopoietic cell transplantation (HCT) practices differ from those of adults, particularly the heterogeneity of transplantable nonmalignant diseases and the lower incidence of graft-versus-host disease (GVHD). Several guidelines regarding the management of acute (a) GVHD in adult HCT have been published. We aimed to capture the real-life approaches for pediatric aGVHD prophylaxis/treatment, and data from 75/193 (response rate 39%) EBMT centers (26 countries) were included, representing half (48%) of the pediatric EBMT-HCT activity. Results with ≥75% approval from respondents (74/75) for GVHD prophylaxis after myeloablative HCT for malignancies partially contradict published guidelines: Single-agent cyclosporine A (CsA) was used for matched sibling donor HCT in 47%; blood CsA levels were reported lower; the relapse risk in malignant diseases influenced GVHD prophylaxis with early withdrawal of CsA; distinct longer duration of CsA was employed in nonmalignant diseases. Most centers used additional anti-thymocyte globulin for matched unrelated and mismatched donor HCT, but not for matched siblings. Regarding prophylaxis in nonmyeloablative conditioning (mainly for nonmalignant diseases), responses showed broad heterogeneity. High conformity was found for first-line treatment; however, results regarding steroid-refractory aGVHD indicate an earlier diagnosis in children. Our findings highlight the need for standardized pediatric approaches toward aGVHD prophylaxis/treatment differentiated for malignant and nonmalignant underlying diseases.
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http://dx.doi.org/10.1111/tri.13601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384018PMC
July 2020

Supportive care during pediatric hematopoietic stem cell transplantation: beyond infectious diseases. A report from workshops on supportive care of the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT).

Bone Marrow Transplant 2020 06 6;55(6):1126-1136. Epub 2020 Feb 6.

Division for Stem Cell Transplantation and Immunology, Department for Children and Adolescents, University Hospital, Goethe University, Frankfurt am Main, Germany.

Hematopoietic stem cell transplantation (HSCT) is currently the standard of care for many malignant and nonmalignant blood diseases. As several treatment-emerging acute toxicities are expected, optimal supportive measurements critically affect HSCT outcomes. The paucity of good clinical studies in supportive practices gives rise to the establishment of heterogeneous guidelines across the different centers, which hampers direct clinical comparison in multicentric studies. Aiming to harmonize the supportive care provided during the pediatric HSCT in Europe, the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT) promoted dedicated workshops during the years 2017 and 2018. The present paper describes the resulting consensus on the management of sinusoidal obstructive syndrome, mucositis, enteral and parenteral nutrition, iron overload, and emesis during HSCT.
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http://dx.doi.org/10.1038/s41409-020-0818-4DOI Listing
June 2020

Outcome of children relapsing after first allogeneic haematopoietic stem cell transplantation for acute myeloid leukaemia: a retrospective I-BFM analysis of 333 children.

Br J Haematol 2020 05 3;189(4):745-750. Epub 2020 Feb 3.

Division of Pediatric Hematology and Oncology, Department of Pediatrics, Universities of Medical University Hannover, Hannover, Germany.

Outcome of 333 children with acute myeloid leukaemia relapsing after a first allogeneic haematopoietic stem cell transplantation was analyzed. Four-year probability of overall survival (4y-pOS) was 14%. 4y-pOS for 122 children receiving a second haematopoietic stem cell transplantation was 31% and 3% for those that did not (P = <0·0001). Achievement of a subsequent remission impacted survival (P = <0·0001). For patients receiving a second transplant survival with or without achieving a subsequent remission was comparable. Graft source (bone marrow vs. peripheral blood stem cells, P = 0·046) and donor choice (matched family vs. matched unrelated donor, P = 0·029) positively impacted survival after relapse. Disease recurrence and non-relapse mortality at four years reached 45% and 22%.
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http://dx.doi.org/10.1111/bjh.16441DOI Listing
May 2020

Long-Term Recipient Health-Related Quality of Life and Donor-Recipient Relationship following Sibling Pediatric Hematopoietic Stem Cell Transplantation.

Biol Blood Marrow Transplant 2020 02 14;26(2):401-406. Epub 2019 Oct 14.

Department of Pediatric Oncology, Hematology and Transplantology, Poznan University of Medical Sciences, Poznan, Poland.

Despite the fact that the choice of donors and the number of sources of hematopoietic stem cells have increased, a sibling remains a preferred donor for allogeneic hematopoietic stem cell transplantation (HSCT). Transplant donation between siblings is a unique life experience that may have an impact on their future relationship. The aim of the study was to quantitatively measure the quality of life (QoL) in patients who underwent transplant and to describe the relationship between a recipient and a sibling donor after HSCT. We identified and invited 82 adults aged 18.0 to 38.7 years (median, 23.6) who underwent HSCT in our center and their sibling donors to participate in this survey. Forty-five patients (54.9%) and their siblings consented to take part in the study. The studied group consisted of 45 matched siblings donor (MSD)-HSCT recipients (19 women and 26 men) aged 18.0 to 36.2 (median, 28.5) years, who underwent MSD-HSCT at the age of 5.8 to 16.3 (median, 11.9) years, and their sibling donors aged 21.0 to 36.0 (median, 31.0) years, who were aged 11.2 to 20.2 (median, 15.5) years at bone marrow harvesting. For QoL and sibling relationship assessment, we used the Functional Assessment of Cancer Therapy-Bone Marrow Transplantation (FACT-BMT) and the Adult Sibling Relationship Questionnaire (ASQR). Higher scores indicate better quality of life in each scale of the FACT-BMT and the more significant is the factor in a sibling relationship measured by the ASQR. The questionnaires were given to both subgroups, HSCT recipients and donors, and the results were compared with each other. The overall result of the FACT-BMT questionnaire was 117 ± 35.0. The highest QoL was found in the functional (25.0 ± 3.5) and social well-being (25.0 ± 3.5) subscales, whereas the worst was in the emotional well-being (18.0 ± 9.5) subscale. Statistically, the QoL score was not influenced by current age (P = .378), age at the moment of HSCT (P = .256), and sex (P = .117). Being a recipient or a donor of HSCT was not a significant factor associated with warmth (2.6 ± 0.5 versus 3.1 ± 0.5; P = .830) and conflict (2.0 ± 0.7 versus 2.1 ± 1.2; P = .886) within the sibling relationship, whereas recipients scored significantly lower in rivalry within the sibling relationship compared with HSCT donors (0.8 ± 0.3 versus 1.2 ± 0.2; P = .012). The FACT Treatment Outcome Index remained the only significant predictor of warmth in the sibling relationship between HSCT recipient and donor. QoL in adult patients after HSCT in childhood was good. Sibling donor-recipient relationship is unbalanced, with a higher level of rivalry presented among donors. Further multicenter studies based on a larger cohort of patients are necessary to assess all aspects of the sibling relationship after transplantation experience.
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http://dx.doi.org/10.1016/j.bbmt.2019.10.009DOI Listing
February 2020

Infection profile in children and adolescents with bone marrow failures treated with allogeneic hematopoietic stem cell transplantation.

Pediatr Transplant 2019 12 6;23(8):e13592. Epub 2019 Oct 6.

Department of Pediatric Hematology and Oncology, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland.

Background: The objective of the study was to analyze the profile of infections in children with BMF following alloHCT.

Methods: Data of 169 consecutive children with inherited and acquired BMF treated with alloHCT between 2012 and 2017 in Polish pediatric transplant departments were analyzed in registry-based retrospective study, with respect to the type of infection, and clinical outcome.

Results: At least 1 infection was diagnosed in 107/169 patients (60.4%). In total, 182 infections were diagnosed. The most common were VI (96; 52.7%), followed by BI (71; 39.0%), and FI (15; 8.2%), P < .001. The most common etiological factors of VI were as follows: CMV (38.5%), EBV (22.9%), and BK virus (24%); while of BI were as follows: Staphylococcus spp. (17; 23.9%), Enterococcus faecium (10; 14.1%), and Klebsiella pneumoniae (9; 12.7%). No difference was found between the occurrence of infections with respect to donor type, graft source, and conditioning type. GvHD had no impact on the incidence of VI, BI, and FI. Fifteen FI were diagnosed in 12 patients, of which 14 FI were diagnosed in children transplanted for FA. Of total 107 children, 9 died (8.4%), of which 4 (3.7%) due to infections: bacterial sepsis (2) and invasive FI (2).

Conclusion: Infections in children with BMF following alloHCT remain an important cause of morbidity. Children with FA had high incidence of FI. In our analysis, aGvHD had no impact on the occurrence on infections, although the study was not strong enough to prove such a difference.
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http://dx.doi.org/10.1111/petr.13592DOI Listing
December 2019

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

Hematol Oncol 2019 Dec 11;37(5):609-616. Epub 2019 Nov 11.

Department of Pediatric Laboratory Diagnostics, Medical University of Bialystok, Białystok, Poland.

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.
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http://dx.doi.org/10.1002/hon.2681DOI Listing
December 2019

Age-dependent determinants of infectious complications profile in children and adults after hematopoietic cell transplantation: lesson from the nationwide study.

Ann Hematol 2019 Sep 18;98(9):2197-2211. Epub 2019 Jul 18.

Department of Hematology, Poznan University of Medical Sciences, Poznan, Poland.

Incidence and outcome of microbiologically documented bacterial/viral infections and invasive fungal disease (IFD) in children and adults after hematopoietic cell transplantation (HCT) were compared in 650 children and 3200 adults in multicenter cross-sectional nationwide study. Infections were diagnosed in 60.8% children and 35.0% adults, including respectively 69.1% and 63.5% allo-HCT, and 33.1% and 20.8% auto-HCT patients. The incidence of bacterial infections was higher in children (36.0% vs 27.6%; p < 0.0001). Infections with Gram-negative bacteria were more frequent than Gram-positives in adults (64.6% vs 44.8%; p < 0.0001). Outcome of bacterial infections was better in children (95.5% vs 91.4%; p = 0.0011). The IFD incidence (25.3% vs 6.3%; p < 0.0001) and outcome (88.0% vs 74.9%; p < 0.0001) were higher in children. The incidence of viral infections was higher in children after allo-HCT (56.3% vs 29.3%; p < 0.0001), and auto-HCT (6.6% vs 0.8%; p < 0.0001). Outcome of viral infections was better in children (98.6% vs 92.3%; p = 0.0096). Infection-related mortality was 7.8% in children and 18.4% in adults (p < 0.0001). No child after auto-HCT died of infection. Adult age, mismatched transplants, acute leukemia, chronic GVHD, CMV reactivation, infection with Gram-negatives, and duration of infection > 21 days were risk factors for death from infection. In conclusion, pediatric patients have 2.9-fold higher incidence and 2.5-fold better outcome of infections than adults after HCT.
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http://dx.doi.org/10.1007/s00277-019-03755-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700048PMC
September 2019

Transplantation in Children and Adolescents with Acute Lymphoblastic Leukemia from a Matched Donor versus an HLA-Identical Sibling: Is the Outcome Comparable? Results from the International BFM ALL SCT 2007 Study.

Biol Blood Marrow Transplant 2019 11 15;25(11):2197-2210. Epub 2019 Jul 15.

St Anna Children's Hospital, UKKJ, MUW, Vienna, Austria.

Eligibility criteria for hematopoietic stem cell transplantation (HSCT) in acute lymphoblastic leukemia (ALL) vary according to disease characteristics, response to treatment, and type of available donor. As the risk profile of the patient worsens, a wider degree of HLA mismatching is considered acceptable. A total of 138 children and adolescents who underwent HSCT from HLA-identical sibling donors (MSDs) and 210 who underwent HSCT from matched donors (MDs) (median age, 9 years; 68% male) in 10 countries were enrolled in the International-BFM ALL SCT 2007 prospective study to assess the impact of donor type in HSCT for pediatric ALL. The 4-year event-free survival (65 ± 5% vs 61 ± 4%; P = .287), overall survival (72 ± 4% versus 68 ± 4%; P = .235), cumulative incidence of relapse (24 ± 4% versus 25 ± 3%; P = .658) and nonrelapse mortality (10 ± 3% versus 14 ± 3%; P = .212) were not significantly different between MSD and MD graft recipients. The risk of extensive chronic (cGVHD) was lower in MD graft recipients than in MSD graft recipients (hazard ratio [HR], .38; P = .002), and the risks of severe acute GVHD (aGVHD) and cGVHD were higher in peripheral blood stem cell graft recipients than in bone marrow graft recipients (HR, 2.06; P = .026). Compared with the absence of aGVHD, grade I-II aGVHD was associated with a lower risk of graft failure (HR, .63; P = .042) and grade III-IV aGVHD was associated with a higher risk of graft failure (HR, 1.85; P = .020) and nonleukemic death (HR, 8.76; P < .0001), despite a lower risk of relapse (HR, .32; P = .021). Compared with the absence of cGVHD, extensive cGVHD was associated with a higher risk of nonleukemic death (HR, 8.12; P < .0001). Because the outcomes of transplantation from a matched donor were not inferior to those of transplantation from an HLA-identical sibling, eligibility criteria for transplantation might be reviewed in pediatric ALL and possibly in other malignancies as well. Bone marrow should be the preferred stem cell source, and the addition of MTX should be considered in MSD graft recipients.
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http://dx.doi.org/10.1016/j.bbmt.2019.07.011DOI Listing
November 2019

Risk Factors for Transplant Outcomes in Children and Adolescents with Non-Malignant Diseases Following Allogeneic Hematopoietic Stem Cell Transplantation.

Ann Transplant 2019 Jun 25;24:374-382. Epub 2019 Jun 25.

Department of Pediatric Hematology, Oncology and Transplantology, Medical University of Lublin, University Children's Hospital, Lublin, Poland.

BACKGROUND The objective of this study was the analysis of transplant outcomes and survival in children treated with allogeneic hematopoietic cell transplantation (alloHCT) for non-malignant disorders, with a focus on risk factor analysis of transplant-related mortality (TRM). MATERIAL AND METHODS The treatment outcome was analyzed retrospectively in 10 consecutive years in 4 pediatric transplant centers in Poland. To compare the outcomes, patient data were analyzed according to the diagnosis, age at transplant, donor type, stem cell source, conditioning regimens, transplanted CD34+ cells dose, and pediatric TRM score. RESULTS From 183 analyzed patients, 27 (14.8%) died, all of them due to transplant-related complications. TRM occurred more frequently in matched unrelated donor (MUD) transplant recipients vs. matched sibling donor (MSD) transplant recipients (p=0.02); in peripheral blood (PB) recipients vs. bone marrow (BM) recipients (p=0.004); and in patients receiving >5×10⁶/kg CD34+ cells (p<0.0001). OS differed significantly according to underlying disease comparing to other diagnoses. Lower survival was found in patients transplanted from MUD (p=0.02). OS was higher in patients receiving BM (p=0.001) and in those receiving ≤5×10⁶/kg CD34+ cells (p<0.001). Multivariate analysis showed lower probability of TRM in BM recipients (p=0.04). The probability of TRM was higher in SCID patients (p=0.02) and in patients receiving >5×10⁶/kg CD34+ cells (p=0.0001). CONCLUSIONS Underlying disease, stem cell source, and CD34+ dose higher than 5×10⁶/kg were the most important risk factors for TRM, and they all affected OS.
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http://dx.doi.org/10.12659/AOT.915330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611216PMC
June 2019

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

Leuk Lymphoma 2019 12 28;60(12):3028-3035. Epub 2019 May 28.

Department of Pediatric Hematology and Oncology, Collegium Medicum, Nicolaus Copernicus University Torun, Bydgoszcz, Poland.

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 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% ( = 190) children including 85.1% ( = 504) episodes of BI, 8.3% ( = 49) - IFD and 6.6% ( = 39) - VI. Among 61 patients with rel/ref AML, at least one IC was found in 67.2% ( = 41) of children including 78.8% ( = 78) of BI, 14.1% ( = 14) of IFD and 7.1% ( = 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.
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http://dx.doi.org/10.1080/10428194.2019.1616185DOI Listing
December 2019

Creation and analysis of biochemical constraint-based models using the COBRA Toolbox v.3.0.

Nat Protoc 2019 03;14(3):639-702

Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belvaux, Luxembourg.

Constraint-based reconstruction and analysis (COBRA) provides a molecular mechanistic framework for integrative analysis of experimental molecular systems biology data and quantitative prediction of physicochemically and biochemically feasible phenotypic states. The COBRA Toolbox is a comprehensive desktop software suite of interoperable COBRA methods. It has found widespread application in biology, biomedicine, and biotechnology because its functions can be flexibly combined to implement tailored COBRA protocols for any biochemical network. This protocol is an update to the COBRA Toolbox v.1.0 and v.2.0. Version 3.0 includes new methods for quality-controlled reconstruction, modeling, topological analysis, strain and experimental design, and network visualization, as well as network integration of chemoinformatic, metabolomic, transcriptomic, proteomic, and thermochemical data. New multi-lingual code integration also enables an expansion in COBRA application scope via high-precision, high-performance, and nonlinear numerical optimization solvers for multi-scale, multi-cellular, and reaction kinetic modeling, respectively. This protocol provides an overview of all these new features and can be adapted to generate and analyze constraint-based models in a wide variety of scenarios. The COBRA Toolbox v.3.0 provides an unparalleled depth of COBRA methods.
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http://dx.doi.org/10.1038/s41596-018-0098-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635304PMC
March 2019

Infectious complications in children treated for hodgkin and non-hodgkin lymphomas in polish pediatric leukemia/lymphoma study group: incidence, epidemiology and etiology.

Leuk Lymphoma 2019 01 5;60(1):124-132. Epub 2018 Nov 5.

c Department of Paediatric Haematology and Oncology , Collegium Medicum, Nicolaus Copernicus University Torun , Bydgoszcz , Poland.

The objective of this nation-wide study was to evaluate the epidemiology and profile of bacterial (BI), viral (VI), and invasive fungal disease (IFD) in patients treated for non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) between the years 2013-2015. In the analyzed period of time, within the studied group of 328 children diagnosed and treated for lymphomas, at least one infectious complication (IC) was diagnosed i.e. 39.3% children. In these patients there were 350 episodes of IC, therein 80.6% episodes of BI, 11.1% episodes of VI, and 8.3% episodes of IFD. In both groups, NHL and HL patients, a stable level of bacterial infections, with an increase in resistance rates, and increased levels of viral and fungal infections were observed. Profile of BI does not depend on lymphoma type, with predominance of Gram-negative bacteria and higher prevalence of MDR pathogens. The overall survival of lymphoma patients with IC was comparable for different types of infections.
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http://dx.doi.org/10.1080/10428194.2018.1466293DOI Listing
January 2019

Thiopurine methyltransferase activity in children with acute myeloid leukemia.

Oncol Lett 2018 Oct 23;16(4):4699-4706. Epub 2018 Jul 23.

Department of Pediatric Oncology, Hematology and Transplantology, Poznan University of Medical Sciences, 60-572 Poznań, Poland.

Activity of the enzyme thiopurine methyltransferase (TPMT) determines the anti-leukemic effect of thiopurines used in the chemotherapy of acute lymphoblastic leukemia (ALL) and acute myeloblastic leukemia (AML). TPMT status and its effects on treatment outcome have been studied extensively in ALL and autoimmune disorders, but few data is available on TPMT in AML. The present study assessed the genetic polymorphisms and activity of TPMT in children with AML at different treatment stages, and compared the results with those obtained for children with ALL. The study included 33 children with AML (0.7-19.7 years) treated with 6-thioguanine (6-TG) according to the AML-BFM 2004 Protocol. Blood samples were collected at diagnosis, during and following maintenance chemotherapy from 8, 10 and 17 patients with AML (the assay was performed at two time points in 2 patients), respectively. Blood samples from 105 children with ALL were obtained at diagnosis, during the maintenance chemotherapy and following the cessation of the chemotherapy from 16, 55 and 34 children, respectively. The activity of TPMT in red blood cells lysates was measured using an enzymatic reaction based on the conversion of 6-mercaptopurine into 6-methylmercaptopurine, involving S-adenozyl-L-methionine as the methyl group donor. TPMT mutations were determined using a polymerase chain reaction/restriction fragment length polymorphism method. Median TPMT activity at diagnosis, during maintenance chemotherapy and following chemotherapy was 43.1, 47,3 and 41.7 nmol 6-mMP g Hb h, respectively. All patients with AML exhibited the homozygous TPMT*1/*1 genotype, with the exception of 1, who was a heterozygote with the TPMT*1/*3C genotype and demonstrated a TPMT activity level at diagnosis of 42.5 nmol 6-mMP g Hb h. At each chemotherapy stage, the median TPMT activities in children with AML were significantly increased compared with the median TPMT activities in children with ALL. The preliminary results suggest that the TPMT activity in AML may be increased compared with that in ALL. Comprehensive studies on the association between thiopurine metabolism and treatment outcome in AML are required, with regard to the cytogenetic and molecular factors currently used for AML risk stratification.
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http://dx.doi.org/10.3892/ol.2018.9191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6126151PMC
October 2018

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.

Transfus Apher Sci 2018 Jun 16;57(3):316-322. Epub 2018 May 16.

Department of Pediatric Oncology, Hematology and Transplantology, II Pediatric Department, Poznan University of Medical Sciences, Poland.

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.
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http://dx.doi.org/10.1016/j.transci.2018.05.012DOI Listing
June 2018

Allogeneic Stem Cell Transplantation from HLA-Mismatched Donors for Pediatric Patients with Acute Lymphoblastic Leukemia Treated According to the 2003 BFM and 2007 International BFM Studies: Impact of Disease Risk on Outcomes.

Biol Blood Marrow Transplant 2018 09 14;24(9):1848-1855. Epub 2018 May 14.

St. Anna Children's Hospital, Universitätsklinik für Kinder- und Jugendheilkunde, Medizinische Universität Wien, Vienna, Austria.

Allogeneic hematopoietic stem cell transplantation (HSCT) is beneficial for pediatric patients with relapsed or (very) high-risk acute lymphoblastic leukemia (ALL) in remission. A total of 1115 consecutive patients were included in the ALL SCT 2003 BFM study and the ALL SCT 2007 I-BFM study and were stratified according to relapse risk (standard versus high versus very high risk of relapse) and donor type (matched sibling versus matched donor versus mismatched donor). A total of 148 patients (60% boys; median age, 8.7 years; B cell precursor ALL, 75%) were transplanted from mismatched donors, which was defined as either less than 9/10 HLA-compatible donors or less than 5/6 unrelated cord blood after myeloablative conditioning regimen (total body irradiation based, 67%) for high relapse risk (HRR; n = 42) or very HRR (VHRR) disease (n = 106). The stem cell source was either bone marrow (n = 31), unmanipulated peripheral stem cells (n = 28), T cell ex vivo depleted peripheral stem cells (n = 59), or cord blood (n = 25). The median follow-up was 5.1 years. The 4-year rates of overall survival (OS) and event-free survival were 56% ± 4% and 52% ± 4%, respectively, for the entire cohort. Patients transplanted from mismatched donors for HRR disease obtained remarkable 4-year OS and event-free survival values of 82% ± 6% and 80% ± 6%, respectively, whereas VHRR patients obtained values of 45% ± 5% and 42% ± 5% (P < .001), respectively. The cumulative incidence of relapse was 29% ± 4% and that of nonrelapse mortality 19% ± 3%. The cumulative incidence of limited and extensive chronic graft-versus-host disease was 13% ± 3% and 15% ± 4%, respectively, among the 120 patients living beyond day 100. Multivariate analysis showed that OS was lower for transplanted VHRR patients (P = .002; hazard ratio [HR], 3.62; 95% confidence interval [CI], 1.60 to 8.20) and for patients beyond second complete remission (CR2) versus first complete remission (P < .001; HR, 3.68; 95% CI, 1.79 to 7.56); relapse occurred more frequently in patients with VHRR disease (P = .026; HR, 3.30; 95% CI, 1.16 to 9.60) and for those beyond CR2 (P = .005; HR, 4.16; 95% CI, 1.52 to 10.59). Nonrelapse mortality was not significantly higher for cytomegalovirus-positive recipients receiving cytomegalovirus-negative grafts (P = .12; HR, 1.96; 95% CI, .84 to 4.58). HSCT with a mismatched donor is feasible in pediatric ALL patients but leads to inferior results compared with HSCT with better matched donors, at least for patients transplanted for VHRR disease. The results are strongly affected by disease status. The main cause of treatment failure is still relapse, highlighting the urgent need for interventional strategies after HSCT for patients with residual leukemia before and/or after transplantation.
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http://dx.doi.org/10.1016/j.bbmt.2018.05.009DOI Listing
September 2018

Relationship between exposure to treosulfan and its monoepoxytransformer - An insight from population pharmacokinetic study in pediatric patients before hematopoietic stem cell transplantation.

Eur J Pharm Sci 2018 Jul 27;120:1-9. Epub 2018 Apr 27.

Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Święcickiego 6 St, 60-781 Poznań, Poland. Electronic address:

Treosulfan (TREO), a structural analog of busulfan, is currently studied as a myeloablative agent in conditioning regimens before hematopoietic stem cell transplantation in pediatric patients. High exposure to TREO (>1650 mg∗h/mL) might be related to early toxicity, especially skin toxicity and mucositis. The aim of the present study was to investigate a potential relationship between exposure to TREO and its monoepoxytransformer (S,S-EBDM), as well as variability of the pharmacokinetics of these entities by means of a population pharmacokinetic approach with a non-linear mixed-effects analysis. The study included data from 14 children with malignant and non-malignant diseases treated with TREO in daily doses 10-14 g/m. The parent-metabolite population pharmacokinetic model was developed in NONMEM 7.3 software. Upon the constructed model, an extensive simulation was performed to assess the correlation between exposure to TREO and S,S-EBDM. It was found that TREO and S,S-EBDM pharmacokinetics was best described with 2-compartmental and 1-compartmental linear models, respectively. The vast majority (>65%) of TREO was transformed to S,S-EBDM. Overall, a considerable interpatient variability of pharmacokinetic parameters was observed, especially the clearance of S,S-EBDM. A weak correlation was found between the exposure to TREO and S,S-EBDM (r = 0.1681, p < 0.0001). Also, patients with an exposure to TREO above 1650 mg∗h/mL were most likely to have also a high exposure to S,S-EBDM (35.38 μM∗h vs. 43.14 μM∗h, p < 0.0001). In summary, a parent-metabolite population pharmacokinetic model for TREO and S,S-EBDM was developed for the first time. It was shown that there is a weak correlation between exposure to TREO and S,S-EBDM. Therefore therapeutic drug monitoring of not only prodrug but also its active epoxide might be needed.
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http://dx.doi.org/10.1016/j.ejps.2018.04.036DOI Listing
July 2018