Diagnosis and treatment of juvenile myelomonocytic leukemia in Slovak Republic: novel approaches.

Juvenile myelomonocytic leukemia (JMML) is a rare, aggressive clonal myeloproliferative disorder of infancy and early childhood caused by oncogenic mutations in genes involved in the Ras pathway. Long-term survival has only been achieved with hematopoietic stem cell transplantation (HSCT), being able to cure more than 50% patients. To manage the disease before HSCT remains an important issue with constant searching for optimal treatment modalities. According to several retrospective analyses, azacitidine (AZA) induced clinical and molecular responses in patients with relapsed JMML pre-transplant and post-transplant, suggesting its use as a promising "bridging" therapy before HSCT. In this paper we report our first consecutive cohort of patients with JMML treated at our institution as well as our experience with the diagnosis, novel treatment and management of these patients before the HSCT. We present 6 patients with JMML, harboring different somatic mutations (PTPN11 and NRAS), with distinct clinical features; 3 of them had been treated with AZA 75 mg/m2 i.v. on days 1 to 7 of a 28-day cycle before the HSCT. Response to therapy was evaluated after each cycle in accordance with the International response criteria. One patient had a progression of splenomegaly during the treatment and after three cycles he was urgently transplanted. At the present, he is remaining in complete remission 3 years after HSCT. Two patients showed impressive response following the first cycle of the therapy with a regression of splenomegaly and monocyte count, normalized leukocytes, platelets and absent blasts in peripheral blood. The treatment was well tolerated with no adverse effect recorded. The clinical activity and favorable toxicity of AZA in JMML provide a rationale for its use as a "bridging" therapy before HSCT. Prospective trials with accompanying translational studies are required to provide further information regarding individual factors that may direct the most appropriate choice of pretransplantation therapy.

Non-anaplastic peripheral T cell lymphoma in children and adolescents-an international review of 143 cases.

Peripheral T cell lymphomas (PTCL) are rare in children and adolescents, and data about outcome and treatment results are scarce. The present study is a joint, international, retrospective analysis of 143 reported cases of non-anaplastic PTCL in patients <19 years of age, with a focus on treatment and outcome features. One hundred forty-three patients, between 0.3 and 18.7 years old, diagnosed between 2000 and 2015 were included in the study. PTCL not otherwise specified was the largest subgroup, followed by extranodal NK/T cell lymphoma, hepatosplenic T cell lymphoma (HS TCL), and subcutaneous panniculitis-like T cell lymphoma (SP TCL). Probability of overall survival (pOS) at 5 years for the whole group was 0.56 ± 0.05, and probability of event-free survival was (pEFS) 0.45 ± 0.05. Patients with SP TCL had a good outcome with 5-year pOS of 0.78 ± 0.1 while patients with HS TCL were reported with 5-year pOS of only 0.13 ± 0.12. Twenty-five percent of the patients were reported to have a pre-existing condition, and this group had a dismal outcome with 5-year pOS of 0.29 ± 0.09. The distribution of non-anaplastic PTCL subtypes in pediatric and adolescent patients differs from what is reported in adult patients. Overall outcome depends on the subtype with some doing better than others. Pre-existing conditions are frequent and associated with poor outcomes. There is a clear need for subtype-based treatment recommendations for children and adolescents with PTCL.

First prospective report on immune tolerance in poor risk haemophilia A inhibitor patients with a single factor VIII/von Willebrand factor concentrate in an observational immune tolerance induction study.

INTRODUCTION/BACKGROUND: Development of neutralizing inhibitors against factor VIII (FVIII) is a major complication of haemophilia A treatment. AIM: The ongoing, international, open-label, uncontrolled, observational immune tolerance induction (ObsITI) study evaluates ITI, the standard of care in patients with inhibitors. PATIENTS/METHODS: Forty-eight prospective patients in this interim analysis received a single plasma-derived, von Willebrand factor-stabilized, FVIII concentrate (pdFVIII/VWF) for ITI. According to recommended Bonn protocol, 'low responders' at ITI start (<5 BU) received 50-100 IU FVIII kg(-1) daily, or every other day; 'high responders' (≥5 BU) received 100 IU FVIII kg(-1) every 12 h. RESULTS: Forty of 48 patients (83.3%), had at least one risk factor for poor ITI-prognosis at ITI start (i.e. age ≥7 years, >2 years since inhibitor diagnosis, inhibitor titre ≥10 BU at the start of ITI, or prior ITI failure). Nonetheless, 34 patients (70.8%) achieved complete success, 3 (6.3%) partial success, 1 (2.1%) partial response; ITI failed in 10 patients (20.8%), all with poor prognosis factors. All six low responders achieved complete success. ITI outcome was significantly associated with inhibitor titre level at ITI start (P = 0.0068), number of poor prognosis factors for ITI success (P = 0.0187), monthly bleeding rate during ITI (P = 0.0005) and peak inhibitor titre during ITI (P = 0.0007). Twenty-two of 35 high responder patients (62.9%) with ≥1 poor prognosis factor achieved complete success. CONCLUSION: Treatment with a single pdFVIII/VWF concentrate, mainly according to the Bonn protocol, resulted in a high ITI success rate in haemophilia A patients with inhibitors and poor prognosis for ITI success.

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.

Minimal residual disease detection using real-time quantitative PCR analysis of immunoglobulin and T-cell receptor gene rearrangements in the non-MRD-based ALL IC-BFM 2002 protocol for childhood ALL: Slovak experience.

Acute lymphoblastic leukemia is the most common form of cancer in children. The 10-year event-free survival ranged from 77 to 85% after having achieved complete remission rates of 93% or higher. The main cause of treatment failure is relapse arising from outgrowth of residual leukemic cells that are refractory to therapy. An intense effort has been made to develop methods to determine the degree of minimal residual leukemia cells present in patients considered to be in morphological remission. Because of the strong correlation between minimal residual disease (MRD) levels and risk of relapse, monitoring of MRD provides unique information regarding treatment response. The MRD monitoring based on real-time quantitative PCR detection of patient-specific immunoglobulin and T-cell receptor (Ig/TCR) gene rearrangements is currently considered to be the most reliable tool for MRD-based diagnosis in ALL. Because the significance of MRD monitoring has been strongly supported by several studies and because it has been implemented in the latest protocols, there has been a significant effort to develop MRD monitoring in the Slovak Republic since 2005. Between October 2006 and December 2009, 50 children with ALL who were treated at three Slovak centers were included in the RQ PCR MRD pilot project. A total of 40 patients with BCP-ALL ( B cell precursor ALL) and 4 patients with T ALL were analyzed for Ig/TCR rearrangement. We identified 106 different rearrangements in the 44 ALL patients analyzed. Based on MRD stratification, we identified 26 patients who were stratified into the HRG ( high risk group) (n = 3; 11.5%), IRG ( intermediate risk group) (n = 14; 54%) and SRG ) standard risk group) (n = 9; 34.5%). Morphology-based risk stratification allows the identification of most HRG patients identified also by MRD-based stratification, but fails to discriminate the IRG assigned to therapy reduction. Patients in the SRG and the IRG could profit from MRD-based risk assignment

[Immunophenotyping with flow cytometry in patients with acute leukemia]. / Imunofenotypizácia prietokovým cytometrom u pacientov s akútnou leukémiou.

The authors evaluate their own results of examinations using a flow cytometer in 72 patients (22 children and 50 adults) with acute leukaemia, incl. 34 acute lymphatic leukaemias and 38 acute myeloid leukaemias during the period between January 1994 and October 1995. At the same time the authors draw attention to the clinical importance in the diagnosis, treatment and prognosis as well as to different findings in children and adults.

Partial trisomy of 3q detected by chromosome painting in a case of juvenile chronic myelomonocytic leukemia.

Juvenile chronic myelomonocytic leukemia (JCMMoL) is a rare disease with no specific type of chromosome aberration yet delineated. We report a 2-year-old boy who had in his leukemic bone marrow (BM) and peripheral blood (PB) cells the 46,XY,der(15)t(3;15)(q13.1;q26) karyotype. Phytohemagglutinin (PHA)-stimulated lymphocytes of peripheral blood had a normal 46,XY karyotype. The origin of the duplicated part of 3q was proved by fluorescence in situ hybridization (FISH) with the pHSR(sat III 15p) DNA probe and a chromosome 3-specific DNA library (i.e., chromosome painting). The chromosome finding in our case provides further proof of the close relationship between the rearrangement in region 3q13-->3q26 and the pathogenesis of acute myeloid leukemia (AML). Our patient has transformed into erythroleukemia [M6 according to the French-American-British (FAB) classification] during the course of the disease.

Fluconazole in children: first experience with prophylaxis in chemotherapy-induced neutropenia in pediatric patients with cancer.

In an open multicenter, prospective study fluconazole (FLU) was administered to prevent fungal infection in 22 neutropenic, 2- to 14-year-old children. Of 4 failures, one was infected with an Aspergillus spp., one with Candida krusei and one with Candida (Torulopsis) glabrata. One failure was of bacterial origin. Those patients with mycoses who failed on fluconazole were successfully treated with other antifungals. In 4 patients transient elevation of liver enzymes was observed. This is the first reported trial using FLU in prophylaxis against fungal infection in neutropenic pediatric patients, where 18/24 children did not present any evidence of mycotic infection using FLU in daily doses of 1-4 mg/kg.

[Results of treatment of acute lymphoblastic leukemia over a 12-year period]. / Výsledky liecby akutnej lymfoblastickej leukémie za 12-rocné obdobie.

In the course of a 12-year period the authors treated at the Paediatric Department of the Regional Institute of National Health in Banská Bystrica 72 children with acute lymphoblastic leukaemia according to four protocols. Complete remission was achieved by 67 children, i.e. 93%. None of the children died from complications of treatment during complete remission. A relapse during treatment or soon after its termination occurred in 23 children, i.e. 31.9%. A second complete remission was achieved in 15 children, i.e. 65.2%. During the second complete remission seven children survive for 0.5-91.5 months. Twenty children died, i.e. 27.8%. All children had at the time of death signs of malignant disease. Fifty-two children survive at present for 1-132 months. The cumulative ratio of surviving children in the 12th year since the diagnosis is 0.57, the cumulative ratio of children in initial complete remission in the 12th year is 0.51.