Tomasz Ociepa

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.

Thrombotic complications of tunneled central lines in children with malignancy.

Background The total rate of thrombotic complications caused by tunneled central lines (TCL) is still not known, as are the long-term consequences. Aim of the Study Estimation of a rate of thrombotic complications in children with TCL and malignancy and Doppler ultrasound assessment of blood flow after TCL removal. Materials and Methods One hundred twenty-four children were enrolled for the study. Heparin lock was used as a prophylaxis for line occlusion. The rate and type of thrombotic events associated with TCL were analyzed in all patients. In children without an earlier history of thrombosis, a Doppler ultrasound examination was carried out after TCL removal. Results In 45.2% of patients at least 1 thrombotic event occurred. These events were TCL lumen thrombosis (42.8% of patients) and subclavian vein thrombosis (2.4% of patients). In 37 patients Doppler ultrasound was carried out and revealed an abnormal blood flow in the vein that was examined in 59.5% of them. Conclusions The total rate of thrombotic complications in children with TCL and malignancy is high. A substantial proportion of thrombotic complications can be clinically silent. The use of a heparin lock once a week seems far from effective in preventing thrombotic events in patients with TCL. The TCL life span has no influence on the rate of thrombotic events.

Asparaginase-associated pancreatitis in childhood acute lymphoblastic leukaemia: an observational Ponte di Legno Toxicity Working Group study

BACKGROUND Survival for childhood acute lymphoblastic leukaemia surpasses 90% with contemporary therapy; however, patients remain burdened by the severe toxic effects of treatment, including asparaginase-associated pancreatitis. To investigate the risk of complications and risk of re-exposing patients with asparaginase-associated pancreatitis to asparaginase, 18 acute lymphoblastic leukaemia trial groups merged data for this observational study. METHODS Patient files from 26 trials run by 18 trial groups were reviewed on children (aged 1·0-17·9 years) diagnosed with t(9;22)-negative acute lymphoblastic leukaemia between June 1, 1996, and Jan 1, 2016, who within 50 days of asparaginase exposure developed asparaginase-associated pancreatitis. Asparaginase-associated pancreatitis was defined by at least two criteria: abdominal pain, pancreatic enzymes at least three times the upper limit of normal (ULN), and imaging compatible with pancreatitis. Patients without sufficient data for diagnostic criteria were excluded. Primary outcomes were defined as acute and persisting complications of asparaginase-associated pancreatitis and risk of re-exposing patients who suffered an episode of asparaginase-associated pancreatitis to asparaginase. Data were collected from Feb 2, 2015, to June 30, 2016, and analysed and stored in a common database at Rigshospitalet, Copenhagen, Denmark. FINDINGS Of 465 patients with asparaginase-associated pancreatitis, 33 (8%) of 424 with available data needed mechanical ventilation, 109 (26%) of 422 developed pseudocysts, acute insulin therapy was needed in 81 (21%) of 393, and seven (2%) of 458 patients died. Risk of assisted mechanical ventilation, need for insulin, pseudocysts, or death was associated with older age (median age for patients with complications 10·5 years [IQR 6·4-13·8] vs without complications 6·1 years [IQR 3·6-12·2], p<0·0001), and having one or more affected vital signs (fever, hypotension, tachycardia, or tachypnoea; 96 [44%] of 217 patients with affected vital signs vs 11 [24%] of 46 patients without affected vital signs, p=0·02). 1 year after diagnosis of asparaginase-associated pancreatitis, 31 (11%) of 275 patients still needed insulin or had recurrent abdominal pain or both. Both the risk of persisting need for insulin therapy and recurrent abdominal pain were associated with having had pseudocysts (odds ratio [OR] 9·48 [95% CI 3·01-35·49], p=0·0002 for insulin therapy; OR 11·79 [4·30-37·98], p<0·0001 for recurrent abdominal pain). Within 8 years of asparaginase-associated pancreatitis, risk of abdominal symptoms dropped from 8% (26 of 312) to 0% (0 of 35) but the need for insulin therapy remained constant (9%, three of 35). 96 patients were re-exposed to asparaginase, including 59 after a severe asparaginase-associated pancreatitis (abdominal pain or pancreatic enzymes at least three times the ULN or both lasting longer than 72 h). 44 (46%) patients developed a second asparaginase-associated pancreatitis, 22 (52%) of 43 being severe. Risk of persisting need for insulin or abdominal pain after having had two versus one asparaginase-associated pancreatitis did not differ (three [7%] of 42 vs 28 [12%] of 233, p=0·51). Risk of a second asparaginase-associated pancreatitis was not associated with any baseline patient characteristics. INTERPRETATION Since the risk of a second asparaginase-associated pancreatitis was not associated with severity of the first asparaginase-associated pancreatitis and a second asparaginase-associated pancreatitis did not involve an increased risk of complications, asparaginase re-exposure should be determined mainly by the anticipated need for asparaginase for antileukaemic efficacy. A study of the genetic risk factors identifying patients in whom asparaginase exposure should be restricted is needed. FUNDING The Danish Childhood Cancer Foundation and The Danish Cancer Society (R150-A10181).

Outcome of refractory and relapsed acute myeloid leukemia in children treated during 2005–2011 – experience of the Polish Pediatric Leukemia/Lymphoma Study Group (PPLLSG)

Aim of the study Recent studies showed relatively better outcome for children with refractory (refAML) and relapsed acute myeloid leukemia (relAML). Treatment of these patients has not been unified within Polish Pediatric Leukemia/Lymphoma Study Group (PPLLSG) so far. The goal of this study is to analyze the results of this therapy performed between 2005–2011. Material and methods The outcome data of 16 patients with refAML and 62 with relAML were analyzed retrospectively. Reinduction was usually based on idarubicine, fludarabine and cytarabine with allogenic hematopoietic stem cell transplant (alloHSCT) in 5 refAML and 30 relAML children. Results Seventy seven percent relAML patients entered second complete remission (CR2). Five-year OS and disease-free survival (DFS) were estimated at 16% and 30%. The outcome for patients after alloHSCT in CR2 (63%) was better than that of those not transplanted (36%) with 5-year OS of 34% vs. 2-year of 7% and 5-year DFS of 40% vs. 12.5%. Second complete remission achievement and alloHSCT were the most significant predictors of better prognosis (p = 0.000 and p = 0.024). The outcome of refAML children was significantly worse than relAML with first remission (CR1) rate of 33%, OS and DFS of 25% at 3 years and 53% at 2 years, respectively. All survivors of refAML were treated with alloHSCT after CR1. Conclusions The uniform reinduction regimen of the documented efficacy and subsequent alloHSCT in remission is needed to improve the outcome for ref/relAML children treated within PPLLSG. The focus should be on the future risk-directed both front and second line AML therapy.

Pediatric pulmonary hodgkin lymphoma: Analysis of 10 years data from a single center

Several reports indicate that lungs are the extralymphatic site most commonly affected in patients with Hodgkin lymphoma; however, the data in children are rather limited. This retrospective study aimed to assess the frequency, clinical picture, and the impact on prognosis in children with pulmonary Hodgkin lymphoma, who were diagnosed and treated in a single center during a 10-year period. Pulmonary lesions related to HL: nodules and parenchymal infiltrates with cavitations were found in 3 of 32 (9.4%) patients; in 2 cases these were found as the concomitant manifestation whereas in 1 case as the solitary form (Primary Pulmonary Hodgkin Lymphoma). B-DOPA and MVPP chemotherapy combined with mediastinal and pulmonary irradiation resulted in sustained remissions in all 3 patients, lasting 3, 7, and 64 months, respectively. Lung involvement occurs in up to 10% of children with Hodgkin lymphoma. Primary pulmonary Hodgkin lymphoma is a rare and atypical form of Hodgkin lymphoma; thus is associated with delayed diagnosis which does not seem to affect prognosis. It should be suspected in a child with non-resolving pneumonia and pulmonary parenchymal infiltrates with cavitations.

Imatinib in the treatment of chronic myeloid leukemia in children and adolescents is effective and well tolerated: Report of the Polish Pediatric Study Group for the Treatment of Leukemias and Lymphomas

BACKGROUND Chronic myeloid leukemia (CML) constitutes only 2-3% of all leukemias in pediatric patients. Philapelphia chromosome and BCR-ABL fusion are genetic hallmarks of CML, and their presence is crucial for targeted molecular therapy with tyrosine kinase inhibitors (TKIs), which replaced hematopoietic stem cell transplantation (HSCT) as a standard first-line therapy. The disease in pediatric population is rare, and despite molecular and clinical similarities to CML in adults, different approach is needed, due to the long lifetime expectancy and distinct developmental characteristics of affected children. OBJECTIVES The objective of this study is to evaluate treatment with imatinib in Polish pediatric patients with CML. MATERIAL AND METHODS We analyzed the results of treatment with imatinib in 57 pediatric patients (June 2006 - January 2016) from 14 Polish pediatric hematology and oncology centers. RESULTS In the study group, 40 patients continued imatinib (median follow-up: 23.4 months), while in 17 the treatment was terminated (median follow-up: 15.1 months) due to therapy failure. In the latter group, 13 patients underwent HSCT, while 4 switched to second-generation TKIs. The 5-year overall survival rate (OS) in the study group was 96%, and the 5-year event-free survival (EFS) was 81%. CONCLUSIONS Our results confirm that the introduction of TKI therapy has revolutionized the treatment of CML in the pediatric population by replacing the previous method of treatment with HSCT and allowing a high percentage of OS and EFS.

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

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

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.

Abnormal correlation of circulating endothelial progenitor cells and endothelin-1 concentration may contribute to the development of arterial hypertension in childhood acute lymphoblastic leukemia survivors.

It is well known that the rate of arterial hypertension (AH) in childhood acute lymphoblastic leukemia (ALL) survivors is significantly higher than that in the healthy pediatric population; however, the mechanism of this phenomenon is not fully understood. The developing cardiovascular system in children is thought to be highly susceptible to the toxic effects of chemotherapy, which causes damage to the blood vessel wall, including the endothelium. Endothelin-1 (ET-1) is a marker of endothelial damage, and it contributes to AH. Endothelial progenitor cells (EPCs) are derived from the bone marrow and participate in the process of blood vessel repair. The aim of this study was to determine the relationship between the rate of circulating EPCs and plasma levels of ET-1 with respect to hypertension in childhood ALL survivors. The study included 88 childhood ALL survivors and 44 healthy children as controls. All patients and controls had 24-h blood pressure monitoring with a HolCARD CR-07 device. The number of EPCs and the ET-1 serum concentration were measured in the peripheral blood of patients and controls using flow cytometry and enzyme-linked immunosorbent assay, respectively. A correlation was found between the number of EPCs and the ET-1 concentration in the peripheral blood of healthy children and normotensive ALL survivors. However, such a correlation was not found in hypertensive childhood ALL survivors. We conclude that dysregulation of the ‘ET-1 and EPC axis’ may contribute to the development of AH in some childhood ALL survivors.

Zespół tylnej odwracalnej encefalopatii w przebiegu leczenia indukcyjnego ostrej białaczki limfoblastycznej u 4-letniego dziecka – opis przypadku

Streszczenie Zespol tylnej odwracalnej encefalopatii ( posterior reversible encephalopathy syndrome – PRES) jest zespolem ostrych objawow neurologicznych, takich jak: bole glowy, zaburzenia widzenia, zaburzenia świadomości, drgawki, ktorym towarzyszą stwierdzane w badaniach obrazowych ośrodkowego ukladu nerwowego (tomografia komputerowa, tomografia rezonansu magnetycznego) charakterystyczne, symetryczne zmiany w istocie bialej i szarej obu polkul, najcześciej platow ciemieniowych i potylicznych. W wiekszości przypadkow objawy zespolu ustepują bez odleglych nastepstw neurologicznych. Przedstawiamy przypadek 4-letniej dziewczynki z ostrymi objawami neurologicznymi, ktore wystąpily w czasie leczenia indukcyjnego ostrej bialaczki limfoblastycznej (o.b.l.). Na podstawie objawow neurologicznych (drgawki, zaburzenia widzenia, zmiany zachowania, zaburzenia świadomości) oraz innych objawow, w tym nadciśnienia tetniczego, upośledzonej funkcji nerek i zmian w badaniach obrazowych ośrodkowego ukladu nerwowego, rozpoznano zespol tylnej odwracalnej encefalopatii. Znajomośc obrazu klinicznego i zmian radiologicznych charakterystycznych dla PRES moze byc pomocna w roznicowaniu innych stanow neurologicznych, ktore mogą wystąpic u dziecka z o.b.l. tj. zajecia ośrodkowego ukladu nerwowego (OUN) przez chorobe podstawową czy krwawienia do OUN.