Krzysztof Czyżewski

Intrathecal therapy with rituximab in central nervous system involvement of post-transplant lymphoproliferative disorder

Abstract Post-transplant lymphoproliferative disorder (PTLD) caused by Epstein–Barr virus (EBV) is a severe complication in high-risk allogeneic hematopoietic stem cell transplant (HSCT) recipients. Central nervous system (CNS) involvement of PTLD is a very rare event in patients with HSCT. As no established standard therapy in CNS-EBV-PTLD is available, the aim of this study was analysis of the safety and efficacy of intrathecal rituximab therapy in a group of eight children and adolescents with CNS-EBV-PTLD. Seven patients responded to therapy: all clinical symptoms and EBV-DNA viral load resolved after a median 2 (range: 1–7) doses of rituximab. However, some magnetic resonance imaging (MRI) changes in brain scan persisted in two patients. In all patients, except one, no adverse events of the therapy were observed. In conclusion, intrathecal rituximab administration seems to be an effective and safe method of treatment of CNS-EBV-PTLD in pediatric stem cell recipients. We recommend this treatment modality for further investigation.

Increased risk of infections and infection-related mortality in children undergoing haematopoietic stem cell transplantation compared to conventional anticancer therapy: a multicentre nationwide study

This nationwide multicentre study analysed the epidemiology of bacterial, viral and fungal infections in paediatric haematopoietic stem cell transplantation (HSCT) and paediatric haematology and oncology (PHO) patients over a period of 24 consecutive months, including incidence, hazard risk and outcome of infections as well as occurrence of multidrug-resistant bacteria. During this period, 308 HSCTs were performed and 1768 children were newly diagnosed for malignancy. Compared to PHO, the risk in HSCT patients was significantly higher for all infections (hazard ratio (HR) 2.7), bacterial (HR 1.4), fungal (HR 3.5) and viral (HR 15.7) infections. The risk was higher in allo- than auto-HSCT for bacterial (HR 1.4), fungal (HR 3.2) and viral (HR 17.7) infections. The incidence of resistant bacteria was higher in HSCT than in PHO patients for both G-negative (72.5% vs. 59.2%) and G-positive (41.4% vs. 20.5%) strains. Cumulative incidence of bacterial, fungal and viral infections in HSCT patients was 33.9, 22.8 and 38.3%, respectively. Cumulative incidence of viral infections in allo-HSCT was 28.0% for cytomegalovirus, 18.5% for BK virus, 15.5% for Epstein-Barr virus, 9.5% for adenovirus, 2.6% for varicella zoster virus, 0.9% for influenza, 0.9% for human herpesvirus 6 and 0.3% for hepatitis B virus. Survival rates from infections were lower in HSCT than in PHO patients in bacterial (96.0 vs. 98.2%), fungal (75.5 vs. 94.6%) and most viral infections. In conclusion, the risk of any infections and the occurrence of resistant bacterial strains in allo-HSCT patients were higher than in auto-HSCT and PHO patients, while the outcome of infections was better in the PHO setting.

Bacterial infections in pediatric hematopoietic stem cell transplantation recipients: incidence, epidemiology, and spectrum of pathogens: report of the Polish Pediatric Group for Hematopoietic Stem Cell Transplantation

Infectious complications are a significant cause of hematopoietic stem cell transplantation (HSCT) failure, especially allogeneic HSCT (allo‐HSCT) because of delayed immune reconstitution and graft‐versus‐host disease (GVHD) occurrence. Identifying the factors responsible for bacterial infections (BI) in patients undergoing HSCT will provide much more effective empirical antimicrobial treatment in this group of patients.

Ex vivo activity of thalidomide in childhood acute leukemia

Thalidomide is a drug with anti-angiogenic, anti-inflammatory, immunomodulatory and anti-cancer properties that were found to inhibit the production of TNF-α in vitro, stimulate reactive oxygen species production, and inhibit VEGFR in acute leukemias. Ex vivo activity of thalidomide as a single agent and in combination with prednisolone or cytarabine in childhood acute leukemias was analyzed. Forty samples of childhood acute lymphoblastic leukemia (ALL) and 13 acute myeloid leukemia (AML) were tested for cytotoxicity by the MTT assay and cell cycle phases by flow cytometry. Control studies were performed on 9 samples of normal lymphocytes and 4 cell lines. A weak anti-leukemic activity of thalidomide against childhood leukemic samples was observed. However, in the presence of thalidomide, cytotoxicity of prednisolone or cytarabine, increased 3.3-fold and 2.7-fold, respectively, in childhood ALL but was not changed in AML. Thalidomide increased apoptosis in lymphoblasts, and modulated cell cycle arrest caused by prednisolone but not cytarabine in childhood acute lymphoblastic leukemia samples. Thalidomide potentiated ex vivo sensitivity of childhood ALL cells to prednisolone and cytarabine, while no sensitization effect was observed in AML cells.

Thalidomide increases in vitro sensitivity of childhood acute lymphoblastic leukemia cells to prednisolone and cytarabine

Abstract.Introduction:Thalidomide is a derivative of glutamic acid with anti-angiogenic, anti-inflammatory, immunomodulatory and anti-cancer properties that was found to inhibit the production of tumor necrosis factor α in vitro, stimulate reactive oxygen species production, and inhibit vascular endothelial growth factor receptor in acute leukemias. The purpose of this study was to determine the in vitro activity of thalidomide as a single agent and in combination with prednisolone or cytarabine in childhood acute lymphoblastic leukemia (ALL).Materials and Methods:Bone marrow samples of 40 childhood ALL patients, normal lymphocytes of 9 healthy adults, and 3 lymphoid cell lines were evaluated for cytotoxicity of thalidomide (alone and in combination with prednisolone and cytarabine) using the MTT assay. Cell cycle analysis was performed by flow cytometry.Results:Thalidomide as a single agent had weak antileukemic activity to the childhood ALL samples. However, in the presence of thalidomide the cytotoxicities of prednisolone and cytarabine were increased 3.3-fold (p<0.001) and 2.7-fold (p=0.002), respectively. Thalidomide increased apoptosis in lymphoblasts and modulated the cell-cycle arrest caused by prednisolone, but not that by cytarabine, in childhood ALL samples.Conclusions:Thalidomide increases in vitro the sensitivity of childhood ALL cells to prednisolone and cytarabine.

Improvement of cure after hematopoietic stem cel transplantations in children

Wstep. Transplantacja komorek krwiotworczych (HSCT) jest wazną metodą terapeutyczną w wielu wrodzonych i nabytych chorobach, w tym nowotworowych, zespolach niewydolności szpiku oraz zaburzeniach immunologicznych i metabolicznych. Celem pracy jest analiza wynikow HSCT w pojedynczym ośrodku pediatrycznym w okresie 12 lat. Pacjenci i metodyka. Analizie poddano wyniki przeszczepien wykonanych w latach 2003-2015 w Klinice Pediatrii, Hematologii i Onkologii w Bydgoszczy. Transplantacje analizowano w trzech przedzialach czasowych: 2004-2007, 2008-2011 oraz 2012-2015. Wyniki. Wykonano 318 HSCT, w tym 186 alloge-nicznych (68 zgodnych rodzinnych i 118 od dawcow alternatywnych) oraz 132 autologiczne. Średnie przezycie po HSCT, wyznaczone metodą Kaplana-Meiera wynioslo 8,1 lat. Calkowite prawdopodobienstwo przezycia (pOS) wynioslo 0,64±0,03; pOS po allo-HSCT wynosi 0,62±0,04, a po auto-HSCT 0,67±0,05. Nie wykazano znamiennych roznic w pOS zarowno po allo-HSCT, jak i po auto-HSCT pomiedzy drugim (2008-2011) i trzecim (2012-2015) analizowanym okresie. Jednakze, pOS bylo wyzsze w dru-gim i trzecim okresie w stosunku do okresu pierwszego (2004-2007), zarowno dla wszystkich pacjentow, jak i u pacjentow po auto-HSCT. W grupie pacjentow allo-HSCT, uzyskano wzrost pOS o ponad 20% (43% vs 66% vs 64% w kolejnych przedzialach czasu; ns). Wnioski. Wyniki HSCT uzyskiwane aktualnie w na-szym ośrodku są porownywalne z wynikami podawanymi w miedzynarodowych rejestrach.

Individualized tumor response testing profile has a prognostic value in childhood acute leukemias: multicenter non-interventional long-term follow-up study

Abstract A total number of 817 children with acute lymphoblastic leukemia (ALL) and 181 with acute myeloblastic leukemia (AML) were assessed for individualized tumor response testing (ITRT) profile as a prognostic factor in long-term follow-up. For each patient, ITRT, initial response to therapy and long-term outcome were assessed. In initial ALL, an impact on long-term response was shown in ITRT for 13 drugs, while in initial AML only for cytarabine. For patients with ALL, a combined five-drug ITRT profile for prednisolone, l-asparaginase, vincristine, cytarabine and daunorubicin or doxorubicin had predictive value for probability of disease-free survival (pDFS) in univariate analysis, whereas in multivariate analysis, bone marrow response by day 33 was the only prognostic factor. For patients with AML, no factor had prognostic value for pDFS in univariate analysis, while ITRT to cytarabine almost reached significance. In conclusion, ITRT can possibly be regarded as a risk factor in childhood acute leukemias.

Impact of CMV and EBV on Immune Recovery After Allogeneic Hematopoietic Cell Transplantation in Children

Background/Aim: Immune recovery is a key factor in the management of patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). This study analyzed the factors contributing to immune reconstitution after allo-HSCT. Patients and Methods: Overall, 65 children with malignant or non-malignant diseases were included in multivariate analyses. Results: The following factors contributed to a faster immune recovery: peripheral blood as a stem cell source and reactivation of CMV infection for CD3+ and CD4+ lymphocyte subpopulations; reactivation of CMV infection for CD8+ subset; donor EBV-IgG+ and no EBV reactivation for CD19 lymphocytes; recipient age below 10 years and peripheral blood as a stem cell source for NK cells. For CD2 and CD4/CD8 ratio no factor was significant in multivariate analysis. Conclusion: Patients receiving a graft from an EBV-IgG-positive donor and not having early EBV post-transplant viremia show faster recovery of the B-cells, while patients with early CMV-DNA-emia have a better re-establishment of T-cell subsets.

High-dose therapy and autologous hematopoietic cel transplantation rescue in children with neuroblastoma and Ewing sarcoma

Background. High-dose therapy (HDT) with autologous stem cell rescue has been recently applied in very-poor-risk pediatric solid tumors. Promising data have become available with the use of high-dose busulfan in neuroblastoma (NBL) and Ewing sarcoma (ES), and with high-dose treosulfan in ES. HDT approach resulted in an encouraging outcome without toxic mortality for high-risk patients. Objective. The objective of this study is to present transplant outcomes, that is disease-free-survival and overall survival in children with high-risk NBL and ES undergoing auto-HSCT. Patients and methods. A total number of 47 NBL and 20 ES auto-HSCT performed between 2004 and 2016 in a single transplant center were included in this analysis. Results. Probability of 3-years pOS was 0.79±0.06 and 0.46±0.14 for NBL and ES patients, respectively. Relapse incidence at 3 years after HSCT was 0.37±0.08 and 0.26±0.11 for NBL and ES patients, respectively. The number of relapses at 3 years after HSCT was 15/47 in NBL and 6/20 in ES. Busulfan-based vs treosulfan-based conditioning in ES patients resulted in lower relapse and death rates. NBL and ES patients transplanted in complete remission (CR1) had lower relapse rates and lower death rates than patients at CR>1. Conclusion. Obtained results of auto-HSCT confirm the therapeutic benefit for children with NBL and ES. Recent reports on current practice of HSCT in Europe indicate HDT with auto-HSCT as a standard of care in pediatric patients with high risk or relapsed NBL and ES.

Micafungin in invasive fungal infections in children with acute leukemia or undergoing stem cell transplantation

Jan Styczynski, Krzysztof Czyzewski, Mariusz Wysocki, Olga Zajac-Spychala, Jacek Wachowiak, Tomasz Ociepa, Tomasz Urasinski, Olga Gryniewicz-Kwiatkowska, Agnieszka Kolodziejczyk-Gietka, Bozenna Dembowska-Baginska, Danuta Perek, Malgorzata Salamonowicz, Lukasz Hutnik, Michal Matysiak, Karolina Siewiera, Jowita Frackiewicz, Krzysztof Kalwak, Wanda Badowska, Zofia Malas, Jolanta Gozdzik, Agnieszka Urbanek-Dadela, Graz_yna Karolczyk, Weronika Stolpa, Grazyna Sobol, Zuzanna Gamrot, Mariola Woszczyk and Lidia Gil Department of Pediatric Hematology and Oncology, Collegium Medicum, Nicolaus Copernicus University Torun, Bydgoszcz, Poland; Department of Pediatric Oncology, Hematology and Transplantology, University of Medical Sciences, Poznan, Poland; Department of Pediatric Hematology and Oncology, Pomeranian Medical University, Szczecin, Poland; Department of Oncology, Children’s Memorial Health Institute, Warszawa, Poland; Department of Pediatric Hematology and Oncology, Medical University, Warszawa, Poland; Department of Pediatric Stem Cell Transplantation, Hematology and Oncology, Medical University, Wroclaw, Poland; Division of Pediatric Hematology and Oncology, Children Hospital, Olsztyn, Poland; Department of Clinical Immunology and Transplantology, Stem Cell Transplant Center, University Children’s Hospital, Jagiellonian University Collegium Medicum, Krakow, Poland; Division of Pediatric Hematology and Oncology, Children Hospital, Kielce, Poland; Department of Pediatric, Division of Pediatric Oncology, Hematology and Chemotherapy, Silesian Medical University, Katowice, Poland; Division of Paediatric Haematology and Oncology, Chorzow Paediatric and Oncology Center, Chorzow, Poland; Department of Hematology, University of Medical Sciences, Poznan, Poland