Improved outcome for children and adolescent with acute lymphoblastic leukemia in the first decade of the 21st century: A report from the Slovak Republic.

Our aim was to analyze event-free (EFS) and overall survival (OS) among children and adolescents with acute lymphoblastic leukemia (ALL) treated with International BFM Intercontinental trial (ALL IC 2002) therapy in the Slovak Republic. In total, 280 children and adolescent age 1 to 18 years were treated with ALL IC BFM 2002 based therapy from 2002 to 2012, which was divided into two periods. During 2002-2007, when patients were actively enrolled in the ALL IC-BFM 2002 trial, and during 2008-2012 when the trial was closed and patients were treated with the same therapy without randomization. Five-year EFS and OS rates were 79% (+/- 2.6%) and 86% (+/- 2.1%), respectively, similar to results obtained in the ALL-BFM 95 trial, which was the basis for ALL IC BFM 2002 therapy. The EFS (p<0.012) and OS (p<0.003) were significantly better than the prior Slovak experience in 1997-2001. Survival is improved in standard and intermediate risk groups, including those age 1 to 6 years, and older; with B-cell or T-cell immunophenotype, and is also excellent for those with good early response. The rate of death in induction, cumulative incidence of death in complete remission and of relapse decreased. However, outcome was suboptimal for patients in the high risk group. Current EFS and OS rates for children and adolescents with ALL in the Slovak Republic resembled those obtained in Western Europe as a result of clinical trial participation, and clinical experience acquired with intensive BFM type treatment.

Avascular necrosis of bone in childhood cancer patients: a possible role of genetic susceptibility.

With the increasing number of paediatric cancer patients and with their prolonged survival, the evidence of a number of serious complications induced by anticancer therapy is rising. Osteonecrosis (ON) of bone is one of these treatment-related effects with a multifactorial pathogenesis. In the past few years, several polymorphisms of candidate genes with possible role in development of this disorder were studied.We summarized potential risk factors leading to increased susceptibility to osteonecrosis of bone development in cancer patients during childhood and to present current knowledge in the field of genetic aspects of this condition (Ref. 86).

Protothecal peritonitis in child after bone marrow transplantation: case report and literature review of paediatric cases.

The case presented here illustrates a protothecal infection caused by Prototheca wickerhamii in a paediatric haematopoietic stem cell recipient followed by a review of the literature of all 13 paediatric cases published since 1980. Protothecosis is a rare disease caused by algae, not described in this setting before. Infection was proven additionally post-mortem from peritoneal dialysis fluid. Even though no death of a paediatric patient due to this infection has been reported and the mortality rate associated with protothecosis is low, our patient died from multiorgan failure as a result of numerous post-transplant complications and a strain of cultivated alga that was highly resistant to antifungal agents. Prototheca spp. show various susceptibility profiles, and there is no direct correlation between in vitro activity and clinical response. There are different treatment regimens described but there are no clear published guidelines of specific therapy of protothecosis. Paediatric cases were successfully treated mostly with amphotericin B and azoles. As the number of immunocompromised patients increases, it is necessary to think more about unusual pathogens such as Prototheca.

Clinical relevance of thiopurine S-methyltransferase gene polymorphisms.

The therapeutic response to thiopurines may result in either severe toxic or inadequate effect based on the interindividual genetic variability. Same drug doses of various anticancer drugs cause considerable interindividual differences in the therapeutic response. Genetic factors have a major impact on effectiveness of several anticancer drugs such as mercaptopurine, 5-fluorouracil, platinum agents, and cyclophosphamide. Heredity related differences in interindividual response to thiopurine therapy represent perhaps the most compelling evidence of pharmacogenomics' usefulness in identification of patients in risk for adverse drug reactions. A number of variations in the gene for thiopurine methyltransferase (TPMT) have been associated with the low activity of this enzyme. Patients with intermediate and low activity of TPMT have a greater incidence of thiopurine toxicity. This minireview summarizes results of studies assessing the role of genetic polymorphisms in the gene encoding TPMT and their relationship to the toxicity of thiopurines.

Establishing the method of chimerism monitoring after allogeneic stem cell transplantation using multiplex polymerase chain reaction amplification of short tandem repeat markers and Amelogenin.

We describe the implementation, optimization, sensitivity determination and first clinical results of polymerase chain reaction (PCR) amplification of polymorphic short tandem repeat (STR) markers and Amelogenin locus coupled with fluorescent detection and capillary electrophoresis in chimerism monitoring of patients transplanted at three different transplant centers using a commercially available multiplex microsatellite assay. The chimerism analysis was performed with genomic DNA extracted from unselected peripheral blood leukocytes of one hundred pediatric and adult patients, who underwent allogeneic stem cell transplantation (SCT) from human leukocyte antigen (HLA) matched or one antigen mismatched related or unrelated donors for malignant (70 patients) and non-malignant (30 patients) diseases. Tested were 79 donor recipient pairs for 15 STR systems and identified an informative marker in all but one of them (98,7%), using 6 selected systems out of these fifteen, that appeared highly informative in our patients population. In 21 sex-mismatched donor recipient pairs we used the Amelogenin locus to distinguish the X and Y chromosome. In sixty-three out of these 100 patients chimerism was regularly analyzed from blood samples taken at various time points after SCT with the median follow up of 17 months. Complete chimerism (CC), maintained over the whole follow-up period, was detected in 24 (38, 1%), stable and decreasing mixed chimerism (MC) in 28 (44, 4%) and increasing MC in 11 patients (17, 5%). Patients with CC, stable and decreasing MC showed a significantly better (p 0,005) overall survival rate (0, 81), compared to those with increasing MC (0, 24). These results demonstrate that STR-based chimerism monitoring with sensitivity above 1% and high informativity (98, 7% of donor recipient pairs) is necessary in establishing the origin of engrafted cells after an allogeneic SCT, in detecting graft rejection and that it may contribute in identifying patients with imminent leukemia relapse.

Imatinib mesylate is effective in children with chronic myelogenous leukemia in late chronic and advanced phase and in relapse after stem cell transplantation.

A multicentric phase 2 study was conducted to determine the efficiency and the tolerance of imatinib mesylate in children with chronic myelogenous leukemia (CML) in advanced phase of the disease, in relapse after stem cell transplantation, or in case of failure to an interferon alpha-based regimen. In all, 30 children from eight European countries were enrolled. In 18 children assessable for hematologic response, imatinib mesylate induced complete hematologic response in eight (80%) of the 10 patients included in chronic phase and in six (75%) of eight enrolled in advanced phase of the disease with acceptable toxicity. In 27 patients assessable for cytogenetic response, imatinib mesylate induced disappearance of Philadelphia chromosome-positive bone marrow cells in 12 (60%) of 20 children included in chronic phase and in two (29%) of seven included in advanced phase. A reduction of the bcr-abl/abl ratio to less than 10(-4) was achieved in 11 (50%) of the children included in chronic phase. Estimated 12-month overall survival rate was 95% (95% CI, 87-100%) for the patients included in chronic phase and 75% (95%CI, 45-100%) for those enrolled in advanced phase. Imatinib mesylate is well tolerated and molecular remission can be achieved in children with CML.

Allogeneic peripheral blood stem cell transplantations in children--a single center experience.

We analyzed 30 peripheral blood stem cell transplantations (PBSCT) from 25 human leukocyte antigen (HLA) matched sibling donors (MSD) and 4 HLA-matched unrelated donors (MUD) in 29 patients, done between November 1996 and March 2003. Patients aged 3 to 17 years underwent allogeneic PBSCT for malignant (16 patients) and non-malignant (13 patients) diseases. Sibling donors aged 3 to 23 years were given granulocyte colony-stimulating factor (G-CSF) 5-10 microg/kg/day for 4 to 5 days. All but one of the 29 donors underwent one single leukapheresis for stem cell collection. The patients received a median of 4.2 x 10(6) CD34+ cells/kg of body weight, they all engrafted after a median of 13.5 days (range 10-25 days). Acute graft-versus-host disease (GVHD) grade II to IV developed in 11 of 26 MSD transplants and in all 4 patients after MUD PBSCT. Eleven of 27 evaluable patients experienced chronic GVHD. After a median follow-up of 662 days, 20 out of 29 patients (69%) are alive, three of them need systemic immunosuppression for chronic GVHD. Six patients experienced relapse of their underlying malignant disease, one of them still alive in complete remission. Two patients died of grade IV acute GVHD and two others due to an opportunistic infection. Based upon our experience, PBSCT is a feasible and safe method for both pediatric donors and patients. It is associated with rapid engraftment, no greater incidence of acute but a higher incidence of chronic GVHD as compared to bone marrow transplantation (BMT) and therefore suitable mainly for children suffering from malignant diseases.

Multicenter randomized study of two once daily regimens in the initial management of community-acquired respiratory tract infections in 163 children: azithromycin versus ceftibuten.

In a randomized trial, we compared the efficacy and toxicity of azithromycin and ceftibuten once daily in the initial (empiric) therapy of proven or suspected community-acquired respiratory tract infections (CARTI) in 163 pediatric patients: 95.5% of those treated with azithromycin and 83.6% of those treated with ceftibuten were cured or improved. Streptococcus pneumoniae was more frequently eradicated in the azithromycin than in the ceftibuten group, whereas gram-negative bacilli were more susceptible to ceftibuten. Elimination rates for Staphylococcus aureus and Haemophilus influenzae were similar; adverse reactions did not differ in both arms. Thus, azithromycin was more effective but equally safe than ceftibuten in the initial therapy of pediatric CARTI.