From 2002 to 2007, the International Berlin-Frankfurt-Münster Study Group conducted a prospective randomized clinical trial (ALL IC-BFM 2002) for the management of childhood acute lymphoblastic ...leukemia (ALL) in 15 countries on three continents. The aim of this trial was to explore the impact of differential delayed intensification (DI) on outcome in all risk groups.
For this trial, 5,060 eligible patients were divided into three risk groups according to age, WBC, early treatment response, and unfavorable genetic aberrations. DI was randomized as follows: standard risk (SR), two 4-week intensive elements (protocol III) versus one 7-week protocol II; intermediate risk (IR), protocol III × 3 versus protocol II × 1; high risk (HR), protocol III × 3 versus either protocol II × 2 (Associazione Italiana Ematologia Oncologia Pediatrica AIEOP option), or 3 HR blocks plus single protocol II (Berlin-Frankfurt-Münster BFM option).
At 5 years, the probabilities of event-free survival and survival were 74% (± 1%) and 82% (± 1%) for all 5,060 eligible patients, 81% and 90% for the SR (n = 1,564), 75% and 83% for the IR (n = 2,650), and 55% and 62% for the HR (n = 846) groups, respectively. No improvement was accomplished by more intense and/or prolonged DI.
The ALL IC-BFM 2002 trial is a good example of international collaboration in pediatric oncology. A wide platform of countries able to run randomized studies in ALL has been established. Although the alternative DI did not improve outcome compared with standard treatment and the overall results are worse than those achieved by longer established leukemia groups, the national results have generally improved.
Lymphomas are the third most common malignant disease in childhood, after leukemia and brain tumors. The aim of this study is to show stratification by gender and age as well as long term survival in ...pediatric patients diagnosed with Non-Hodgkin Lymphoma in our center.Our retrospective analysis included 85 children with newly diagnosed NHL from January 1, 1997 to December 31, 2016. They all have been diagnosed and treated at the Department of Pediatric Hematology and oncology, University Hospital Centre Zagreb.Out of 85 children with newly diagnosed NHL 48 of them suffered from B-cell NHL (n = 48; 56%) while the rest of them had T-cell lymphoblastic lymphoma(T-LBL) (n = 20; 24%) or Anaplastic large-cell lymphoma (ALCL) (n = 17; 20%). There were 25 girls and 50 boys (age 3 – 17 years). Overall survival (OS) for the entire group was 78.82%. Diagnose based survival is in the favor of T-LBL – 85.00% in comparison to 81.25% in B-NHL and 64.71% in ALCL.Our survival rates are not very different from the ones in the other European countries. We expect improved survival rates after introducing novel treatment that would optimize therapeutic effect and at the same time minimize the risk of severe late toxic effects.
AimOur study aimed to determine the overall survival of children with non-Hodgkin T-lymphoblastic lymphoma (T-LBL), analyze and present patient characteristics and initial presentation of their ...disease.MethodsOur study included all patients with T-LBL non-Hodgkin lymphoma treated in the Department of Pediatrics, Division of Hematology and Oncology, University Hospital Centre Zagreb between January 1st, 2002 and December 31st, 2017. Relevant information including general patient data (gender, age at the time of diagnosis), initial clinical presentation (the presence of mediastinal masses, pericardial and pleural effusion, the presence of bone marrow and central nervous system disease) and treatment information (used therapeutic protocol and mortality data) was collected from the available medical documentation. The Kaplan-Meier curve shows patients‘ survival.ResultsOverall, 19 patients were included, 14 of which were male (73.68%) and 5 were female (26.32%). The median age at diagnosis was 10 years. 17 patients (94.44%) presented with mediastinal mass and 9 of them (52.94%) had pleural effusion. At the time of diagnosis, pericardial effusion and superior vena cava syndrome were present in 6 (33.33%) and 3 (16.67%) patients, respectively. Bone marrow involvement was detected in 10 patients (52.63%), whereas CNS involvement in only one (5.26%). 16 out of 19 patients survived (84.21%; 95% CI 67.81–100). Survival was higher for boys (85.71%) than for girls (80%), but the difference was not statistically significant (p = 0.764).ConclusionComparing general epidemiologic data with the one in the available literature we haven’t found a significant deviation of the prevalence of the disease between the sex or the median age of onset of the disease. The result of 90% five-year survival of children with T-LBL in the BFM group study was not repeated in later studies and the overall survival of 84% in our group was consistent with the results reported in the available literature.
BACKGROUND:Invasive candidiasis is increasingly prevalent in premature infants and seriously ill children, and pediatric data on available antifungal therapies are lacking.
METHODS:We conducted a ...pediatric substudy as part of a double-blind, randomized, multinational trial to compare micafungin (2 mg/kg) with liposomal amphotericin B (3 mg/kg) as first-line treatment of invasive candidiasis. Treatment success was defined as clinical and mycologic response at the end of therapy. Statistical analyses were descriptive, as the sample size meant that the study was not powered for hypothesis testing.
RESULTS:One hundred six patients were included in the intent-to-treat population; and 98 patients—48 patients in the micafungin group and 50 patients in the liposomal amphotericin B group—in the modified intent-to-treat population. Baseline characteristics were balanced between treatment groups. Overall, 57 patients were <2 years old including 19 patients who were premature at birth; and 41 patients were 2 to <16 years old. Most patients (91/98, 92.9%) had candidemia, and 7/98 (7.1%) patients had other forms of invasive candidiasis. Treatment success was observed for 35/48 (72.9%) patients treated with micafungin and 38/50 (76.0%) patients treated with liposomal amphotericin B. The difference in proportions adjusted for neutropenic status was −2.4% 95% CI(−20.1 to 15.3). Efficacy findings were consistent, independent of the neutropenic status, the age of the patient, and whether the patient was premature at birth. Both treatments were well tolerated, but with a lower incidence of adverse events that led to discontinuation in the micafungin group (2/52, 3.8%) compared with the liposomal amphotericin B group (9/54, 16.7%) (P = 0.05, Fisher exact test).
CONCLUSIONS:Micafungin seems to be similarly effective and as safe as liposomal amphotericin B for the treatment of invasive candidiasis in pediatric patients. (ClinicalTrials.gov number, NCT00106288).
Abstract 872
ALL IC-BFM 2002 is one of the most successful projects developed by the I-BFM-SG, which is one of the world largest societies involving national leukemia groups. The trial evaluated in a ...randomized manner the impact on outcome of intensified late reinduction in the context of a newly developed risk stratification. The main goal of the trial was improvement of outcome of children with ALL in each of the 3 risk groups (RG).
From Nov 2002-Nov 2007, 5060 eligible pts aged 0–18 yrs with newly diagnosed ALL from Argentina (1270), Chile (558), Croatia (122), Cuba (151), Czech Republic (291), Hong Kong (155), Hungary (259), Israel (292), Poland (908), Serbia (266), Slovakia (137), Slovenia (36), Ukraine (421), Uruguay (96), and Moscow (98) were enrolled in the trial (http:clinicaltrials.gov “NCT00764907”). Stratification into 3 RGs was based on early treatment response (evaluated in PB on day 8 and in BM on days 15 and 33), age, initial WBC, and presence/absence of BCR/ABL or MLL/AF4. Standard Risk (SR) criteria were: < 1,000 blasts/μL in PB day 8 after 7 days of oral prednisone with 1 intrathecal methotrexate (IT-MTX) and age ≥ 1 yr and < 6 yr and initial WBC < 20,000/μL and M1 or M2 marrow on day 15 and M1 marrow on day 33 (all criteria must be fulfilled). Intermediate Risk (IR) criteria were: < 1,000 blasts/μL in PB day 8 and age < 1 yr or ≥ 6 yr and/or WBC ≥ 20,000/μL and M1 or M2 marrow on day 15 and M1 marrow on day 33 (or SR criteria but M3 marrow on day 15 and M1 marrow on day 33). High Risk (HR) criteria were: IR and M3 marrow on day 15, PB on day 8 ≥ 1,000 blasts/μL, M2 or M3 marrow on day 33, translocation t(9;22) BCR/ABL or t(4;11) MLL/AF4 (at least one criterion must be fulfilled). The majority of infants < 1 yr were treated in studies Interfant 99 and Interfant 06. Treatment consisted of protocol I‘/I, SR/IR consolidation with 6-MP and MD MTX 2g/m2 × 4 (with additional IT-MTX in maintenance) for BCP-ALL, 6-MP and HD MTX 5g/m2 × 4 for T-ALL, HR consolidation with 3 HR polychemotherapy blocks. A randomized question was asked in late intensification: SR: would 2 shorter elements (protocol III × 2) be more effective than 1 longer (protocol II × 1) even though the cumulative dose of most drugs is not increased? IR: could the risk of failure be reduced by a third reintensification element (protocol III × 3)? HR: could the use of 3 reintensification elements (protocol III × 3) achieve the same or better results than the HR approach applied in BFM (3 HR blocks + protocol II × 1) or AIEOP (protocol II × 2)? Chemotherapy was concluded by maintenance therapy (6-MP/MTX), making up a total of 2 yrs overall treatment. Prophylactic CNS radiotherapy 12 Gy was applied in T-ALL and HR pts.
With median follow-up 4.9 yr, the 5-yr EFS was 74 ± 1% and 5-yr OS 82 ± 1% for the whole group of 5060 pts. The CR rate was 97%, 255 (5%) children died in remission. The 5-yr EFS/OS was 81 ± 1%/90 ± 1% in 1564 SR pts (30.9% of all pts), 75 ± 1%/83 ± 1% in 2650 IR pts (52.4%) and 55 ± 2%/62 ± 2% in 846 HR pts (16.7%). Randomization rate was 79% of those patients who survived for at least 20 weeks (planned timepoint of randomization). None of the experimental arms achieved significantly better EFS compared to standard treatment.
CI of relapses at 5 yr was 18 ± 1% overall, CI for isolated BM relapse was 12 ± 1%, isolated and combined CNS relapse 4 ± 0.3%, isolated and combined testicular relapse 2 ± 0.2%. Secondary malignancy was diagnosed so far in 26 patients (5-yr CI 0.6 ± 0.1%). Significantly better EFS was achieved in BCP-ALL(75 ± 1%) in comparison with T-ALL (69 ± 1%), girls vs. boys (76 ± 1% vs 72 ± 1%), children aged < 10 yr vs ≥ 10 yr (77 ± 1% vs 65 ± 1%), M1/M2 BM D15 vs. M3(76 ± 1% vs 50 ± 3%). 140 pts with Ph+ALL achieved a EFS of 47 ± 4% Allogeneic HSCT in CR1 was done in 139 pts with 5 -yr DFS of 64 ± 4%.
Although the experimental arm was no better than the traditional one across individual RGs, the majority of participating countries, many of them were new-comers to this intensive therapy, improved their treatment results against previous national studies. The trial confirmed the validity and feasibility of a simple risk stratification of ALL applied in a complex and heterogeneous multinational environment. Despite the great differences between individual countries, the trial set a firm stage for willing national leukemia groups to run collaborative clinical trials in ALL under the umbrella of I-BFM-SG.
Supported by MSM0021620813 and MZ0FNM2005.
No relevant conflicts of interest to declare.
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children younger than 15 years. According to the World Health Organization, there are embryonal, alveolar and pleomorphic types of ...RMS. Most RMS patients present with a tumor mass in the head and neck region, urogenital tract or lower extremities. Unusual clinical presentation of the disease with massive bone marrow infiltration at the disease onset and mimicking hematologic neoplasm is rarely seen. A case is presented of a 14-year-old, previously healthy girl hospitalized for outpatiently detected leukocyte elevation. For the last two weeks, she had complained of fatigue, myalgia and frequent bruising. On admission, clinical examination revealed numerous petechiae and hematomas, enlarged left inguinal lymph node and palpable spleen 2 cm below left costal arch. Laboratory findings showed leukocytosis, anemia and thrombocytopenia. Bone marrow fine needle aspiration (FNA) produced a hypercellular bone marrow sample with suppression of all three hemocytopoiesis lines and bone marrow infiltration with numerous undifferentiated tumor cells. Considering the morphological, cytochemical and phenotypic characteristics, the cytologic diagnosis was: bone marrow infiltration with RMS cells. Abdominal computerized tomography revealed a primary tumor occupying the entire retropeoritoneal space. Tumor biopsy confirmed alveolar subtype of RMS. In conclusion, in cases of bone marrow infiltration with primitive, immature cells, RMS should be considered as differential diagnostic possibility. Adjuvant technologies (cytochemistry, immunocytochemistry, cytogenetic analysis, flow cytometry, and molecular analysis) can be very helpful in diagnostic work-up, and may lead to definitive diagnosis in some cases.
Langerhans' cell histiocytosis (LCH) is a disease characterised by pathologic accumulation and proliferation of histiocytes, cells from the monocyte-macrophage system, in various tissues and organs. ...In this retrospective study we analyzed patients charts treated in the Department of pediatric hematology and oncology at the University Hospital Zagreb with the diagnosis of LCH. Twenty-two children were diagnosed between January 1st 1996 and December 31st 2010, and all were treated with chemotherapy. 19 patients survived (86%) and the remaining 3 (14%), all under the age of 2 with multisystem disease, died. At the time of diagnosis 12 children (55%) presented with single-system disease, the most common were bone lesions in 8 children (36%). All children were treated according to protocols LCH-I and LCH -III. Eight children had mild complications of treatment and the disease itself. Diabetes insipidus remains in 4 children.
Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare type of T-cell lymphoma of CD3+CD8+ phenotype characterized by deep-seated skin nodules or plaques mimicking panniculitis, a result of ...neoplastic lymphocytes infiltrating the subcutaneous fatty tissue. We present a case of a 19-month year old boy with SPTCL diagnosed and successfully treated in our institution. Disease first presented with symptoms of high fever and painful erythematous nodule located below the umbilicus. Later on the infiltrates appeared on the face, legs, arms and the back of the body. As the most decisive in obtaining the diagnosis, skin biopsy showed atypical, small to medium-sized lymphatic cells infiltrating the deeper dermal layers as well as the subcutaneous adipous tissue surrounding the adipocytes. Immunohystochemical analysis showed neoplastic lymphocytes positive for CD2, CD3, CD5, CD7, CD8, Tia-1, granzyme B and perforine, and negative for CD20, CD34, TDT and CD56. No infiltration of blood vessels or epidermis was evident. Specific T-cell lymphomas protocol (EURO-LB 02) was then initiated which resulted with rapid regression of all general and local symptoms. The treatment was completed according to schedule and the child is now, 24 months after the initiation of the treatment, in complete remission.
Lymphomas represent the third most common group of cancers in childhood and adolescence, mature B non Hodgkin's lymphoma (B-NHL) accounting for up to 60% of newly diagnosed patients. The diagnosis of ...specific entities of B-NHL is based on well-defined morphologic analysis, immunophenotyping, cytogenetics and molecular genetics, which determine the optimal treatment strategy. In adult population a major turning point in treatment of B-NHL has been achieved since rituximab, in combination with CHOP has improved the survival rate up to 19%. Rituximab is a chimeric monoclonal antibody that targets CD20, a transmembrane calcium channel expressed on normal and malignant B-cells that mediates cytotoxic, apoptotic and anti-proliferative effects. The effect of rituximab in pediatric population is still not well enough investigated. Based on morphology and immunophenotype of malignant cells, seven children with B-NHL in our institution were eligible for treatment with modified B-NHL-Berlin-Frankfurt-Münster (BFM)-95-based protocol with rituximab administered on day -5. The complete remission was achieved in all seven patients. Six patients are still in complete remission at least 12 months after having finished chemotherapy and one patient relapsed two months after the last cycle and subsequently died. Major adverse effects observed during treatment were prolonged B-cell depletion and myelosuppression. Rituximab in combination with B-NHL-BFM-95 protocol was otherwise well tolerated and proved to be effective in children and adolescents with B-NHL. The number of our patients is too small and the follow-up of a larger group of patients will help in defining the role of rituximab in the treatment of childhood B-NHL.
The incidence and severity of fungal infections in children with malignant diseases treated with intensive chemotherapy or allogeneic hematopoietic cell transplantation on the hematology-oncology ...department Children's Hospital Salata Medical School University of Zagreb is analyzed. The efficacy of antifungal therapy is presented.
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