Pulses of vincristine and dexamethasone in addition to intensive chemotherapy for children with intermediate-risk acute lymphoblastic leukaemia: a multicentre randomised trial.

BACKGROUND: Studies in the 1970s and 1980s suggested that the outcome of childhood acute lymphoblastic leukaemia (ALL) could be improved by intensification of conventional continuation chemotherapy with pulses of vincristine sulfate and steroids. We aimed to investigate the efficacy and toxic effects of vincristine-dexamethasone pulses as an addition to the continuation-therapy phase in a large cohort of children with intermediate-risk disease who were treated with the Berlin-Frankfurt-Münster (BFM) treatment strategy. METHODS: 3109 children, diagnosed with ALL and intermediate-risk features, were enrolled by eight participating organisations in eleven countries. All were treated with very similar protocols based on the BFM treatment strategy, which included induction, consolidation, reinduction, and continuation-therapy phases. At the beginning of the continuation-therapy phase, those patients in complete remission were randomly assigned to either a treatment or a control group. Control patients were given conventional mercaptopurine and methotrexate chemotherapy only. Patients in the treatment arm were also given pulses of vincristine (1.5 mg/m2 weekly for 2 weeks) and dexamethasone (6 mg/m2 daily for 7 days) every 10 weeks for six cycles. The primary outcome measure was disease-free survival. Analysis was by intention to treat. The study is registered at http://www.clinicaltrials.gov with the identifier NCT00411541. FINDINGS: 174 patients (5.6%) relapsed or died in complete remission before randomisation. Of the remaining 2935 patients, 2618 (89.2%) were randomly assigned: 1325 to the treatment group and 1293 to the control group. With median follow-up of 4.8 years, 240 children in the treatment group and 241 in the control group had relapses; 15 in the treatment group and 14 controls died in complete remission or developed second malignant neoplasms. The 5-year and 7-year disease-free survival estimates were 79.8% (SE 1.2) and 77.5% (1.5) in the treatment group and 79.2% (1.2) and 78.4% (1.3) in the control group, respectively. Treatment with pulses of vincristine and dexamethasone was associated with a non-significant 3% relative-risk reduction (hazard ratio 0.97; 95% CI 0.81-1.15; p=0.70). INTERPRETATION: Children with intermediate-risk ALL who received intensive chemotherapy based on BFM protocols did not benefit from intensification of the continuation-therapy phase with a schedule of pulses of vincristine and dexamethasone.

Eligibility for allogeneic transplantation in very high risk childhood acute lymphoblastic leukemia: the impact of the waiting time.

The advantage of allogeneic transplant from compatible related donors versus chemotherapy in children with very-high-risk acute lymphoblastic leukemia in first complete remission was previously demonstrated in an international prospective trial. This study quantified the impact of time elapsed in first remission in the same cohort. Of 357 pediatric patients with very-high-risk acute lymphoblastic leukemia, 259 received chemotherapy, 55 transplantation from compatible related and 43 from unrelated donors. The 5-year disease-free survival was 44.2% overall and 42.5% for chemotherapy only patients. The chemotherapy conditional 5-year disease-free survival increased to 44.4%, 47.6%, 51.7%, and 60.4% in patients who maintained their first remission for at least 3, 6, 9, and 12 months respectively. The overall outcome was superior to that obtained with chemotherapy-only at any time-point. The relative advantage of transplant from compatible related donors in very-high-risk childhood acute lymphoblastic leukemia was consistent for any time elapsed in first remission.

Long term survivors of childhood cancer: cure and care. The Erice statement.

The number of subjects that have successfully completed treatment for a cancer diagnosed during childhood and are entering adulthood is increasing over time. Members of the International Berlin-Frankfurt-Munster (I-BFM) Early and Late Toxicity Educational Committee (ELTEC) invited 45 paediatric cancer experts (representing oncologists, psychologists, nurses, epidemiologists, parents, and survivors) from 13 European countries (with five additional experts from North America) to Erice, Sicily (from October 27 to 29, 2006) to discuss the circumstances in which the word 'cure' should be used when speaking about children with cancer, and when and why continuing follow-up and care may be required. The objective of the gathering was to generate from the personal and professional experience of the participants an overview statement of the group's philosophy of cure and care of survivors of childhood cancer. The ten points reflect what the group considers essential in the survivors' cure and care.

Long-term results of a randomized trial on extended use of high dose L-asparaginase for standard risk childhood acute lymphoblastic leukemia.

PURPOSE: Between September 1991 and May 1997, within the International Berlin-Frankfurt-Muenster Study Group (I-BFM-SG), a randomized study was performed aimed at assessing the efficacy of prolonged use of high-dose l-asparaginase (HD-l-ASP) during continuation therapy in children with standard risk (SR) acute lymphoblastic leukemia (ALL), treated with a reduced BFM-type chemotherapy. PATIENTS AND METHODS: The Italian, Dutch, and Hungarian groups participated in this study denominated IDH-ALL-91, and 494 children were enrolled. Treatment consisted of a BFM-type modified backbone with omission of the IB part in induction and elimination of two doses of anthracyclines during reinduction in both arms at the beginning of continuation therapy. Patients were randomly assigned to receive (YES-ASP) or not (NO-ASP) 20 weekly HD-l-ASP (25,000 IU/m2). RESULTS: The event-free-survival and overall survival probabilities at 10 years for the entire group were 82.5% (1.8) and 90.3% (1.3), respectively. Of the 490 patients eligible for random assignment, 355 (72.4%) were randomly assigned (178 YES-ASP and 177 NO-ASP). After a median follow-up of 9 years, the probability of disease-free survival at 10 years was 87.5% (SE, 2.5) for YES-ASP arm versus 78.7% (SE, 3.3) for NO-ASP arm (P = .03). In multivariate analysis, NO-ASP arm (P = .03), male sex (P = .004), and age older than 10 years (P = .0003) had a significantly adverse impact on outcome. CONCLUSION: In this subset of patients, selected with criteria not including monitoring of minimal residual disease, application of extended HD-l-ASP may improve prognosis, compensating reduced leukemia control that results from adoption of a reduced-intensity BFM-backbone for treatment of children with SR ALL.

Chemotherapy versus allogeneic transplantation for very-high-risk childhood acute lymphoblastic leukaemia in first complete remission: comparison by genetic randomisation in an international prospective study.

BACKGROUND: The dismal prognosis of very-high-risk childhood acute lymphoblastic leukaemia could be improved by allogeneic haemopoietic cell transplantation. We compared this strategy with intensified chemotherapy protocols, with the aim to improve the outcome of children with very-high-risk acute lymphoblastic leukaemia in first complete remission. METHODS: A cooperative prospective study was set up in seven countries. Very-high-risk acute lymphoblastic leukaemia in first complete remission was defined by the presence of at least one of the following criteria: (1) failure to achieve complete remission after the first four-drug induction phase; (2) t(9;22) or t(4;11) clonal abnormalities; and (3) poor response to prednisone associated with T immunophenotype, white-blood-cell count of 100x10(9)/L or greater, or both. Children were allocated treatment by genetic chance, according to the availability of a compatible related donor, and assigned chemotherapy or haemopoietic-cell transplantation. The primary outcome was disease-free survival and analysis was by intention to treat. FINDINGS: Between April, 1995, and December, 2000, 357 children entered the study, of whom 280 were assigned chemotherapy and 77 related-donor haemopoietic-cell transplantation. 5-year disease-free survival was 40.6% (SE 3.1) in children allocated chemotherapy and 56.7% (5.7) in those assigned transplantation (hazard ratio 0.67 [95% CI 0.46-0.99]; p=0.02); 5-year survival was 50.1% (3.1) and 56.4% (5.9), respectively (0.73 [0.49-1.09]; p=0.12). INTERPRETATION: Children with very-high-risk acute lymphoblastic leukaemia benefit from related-donor haemopoietic-cell transplantation compared with chemotherapy. The gap between the two strategies increases as the risk profile of the patient worsens.

DNA content heterogeneity in neuroblastoma analyzed by means of image cytometry and its potential significance.

The aim of this study was to determine the frequency and significance of the tumor DNA content heterogeneity in 33 previously untreated human neuroblastomas. We used image cytometry to selectively analyze neuroblasts by excluding karyorrhectic or stromal cells from cytometric measurements. DNA content heterogeneity with more than one clonal subpopulation on DNA histogram was found in 8 of 33 cases. Of these 8 cases, 4 showed MYCN amplification. Double labeling fluorescent in situ hybridization with probes for the centromeric region of chromosome 2 and MYCN gene was used to confirm the DNA content heterogeneity. DNA content heterogeneity was associated with poorer prognosis in this study (P<0.05). There was a significant correlation between euploidy (di- and tetraploidy) and worse prognosis, but only when heterogeneous neuroblastomas with euploid cell population were assigned to euploid tumors (P=0.006). Our results may explain the conflicting data in the literature regarding ploidy and suggest that DNA content heterogeneity and the presence of a euploid population may predict worse prognosis in neuroblastoma patients.

[Treatment results with ALL-BFM-95 protocol in children with acute lymphoblastic leukemia in Hungary]. / Az ALL-bFM-95 protokollal szerzett hazai eredmények akut lymphoblastos leukaemiás gyermekek kezelésében.

BACKGROUND: In Hungary children (from 1 to 18 years of age) with de novo acute lymphoblastic leukemia were treated from January 1996 to October 2002, according to protocol ALL-BFM-95. AIM: The aim of this study was to evaluate the experience with this protocol, the treatment results according to the risk groups and to compare the Hungarian data with the international results. METHODS: Patients were stratified into 3 risk groups, based on initial white blood cell count, age, immunology, cytogenetics and response to treatment: standard, medium and high risk group. RESULTS: Three hundred sixty eight children entered the study (male-female ratio was 1.27:1, median age 6 years and 4 months). 110 (29.9%) children were in the standard, 210 (57.1%) in the medium and 48 (13%) in the high risk group. Duration of the chemotherapy was 2 years, except of the boys in the standard risk group, their maintenance therapy was 1 year longer. The overall complete remission rate was 93.2%. 20 (5.4%) children died in induction and 5 (1.4%) were non-responders. The 5-year overall survival for all patients was 78.5%, in the standard risk group 93.2%, in the medium risk group 78.4% and in the high risk group 44.5% with a minimum follow up of 1.19 years and median follow up of 4.85 years. From the 368 patients 272 (73.9%) are still in their first complete clinical remission and other 18 children are alive after relapse. In 14.7% of the patients relapse was diagnosed; the most common site was the bone marrow. In one patient second malignancy occurred. The 5-year event free survival for all patients was 72.6%, in the standard risk group 87.6%, in the medium risk group 72.1% and in the high risk group 39.9%. CONCLUSION: The treatment outcome of children with acute lymphoblastic leukemia improved remarkably over the last decades. 78% of children suffering from acute lymphoblastic leukemia could be cured with the ALL-BFM-95 protocol. The Hungarian results are comparable to those achieved by other leukaemia study groups in the world regarding the ALL-BFM-95 protocol.

[Guillain-Barré syndrome in patients treated for Hodgkin disease]. / Guillain-Barré-szindróma kialakulása Hodgkin-kór miatt kezelt betegben.

INTRODUCTION: A 14-year-old boy treated with Hodgkin's disease developed muscular weakness and pain, hypotonia, abolished deep tendon reflexes. Examination of the cerebrospinal fluid showed albuminocytologic dissociation, the characteristic finding of Guillain-Barré syndrome. After high dose steroid treatment complete recovery occurred. DISCUSSION: Paraneoplastic neuropathies may develop in patients with cancer, Guillain-Barré syndrome occurs in patients with active Hodgkin's disease. CONCLUSIONS: Progressive neurological signs may indicate the presence of a malignancy, or in case of chemotherapy shows the activity of the tumour.

[Hungarian experience in the treatment of childhood acute lymphoblastic leukemia] / A gyermekkori akut limfoblasztos leukémia kezelésében elért hazai eredmények.

The Hungarian Pediatric Oncology Study Group treated 362 acute lymphoblastic leukemia patients between 1990 and 1995 using the the ALL-BFM 90 protocol. The modified protocol, ALL-BFM 95, was used later to treat 257 patients. The two protocols were similarly successful to treat low and medium risk cases. However, the ALL-BFM 95 protocoll was more efficient to treat high risk patients and resulted in 10% increase in survival. The Western-European results are superior by 10-15% compared to the Hungarian data mainly due to the relatively high proportion of the early death in Hungary. Improvement of these data can only be expected from the development of the diagnostic potentials and from further improvement of treatment of the high isk patients.

[Nested PCR detection of WT1 expression in the peripheral blood in childhood acute leukemia] / Minimális reziduális betegség monitorozása gyermekkori akut leukémiában a WT1 gén perifériás vérben történô expressziójának nyomonkövetésével.

Detection of minimal residual disease (MRD) in childhood leukemia is not possible by cytomorphology or Southern blotting due to their low sensitivity. On the other hand, the use of DNA markers and PCR amplification is helpful in a smaller proportion of leukemia cases (20-30%). Since childhood leukemia is characterized by WT1 gene expression in the majority of cases,monitoring of WT1 expression in the peripheral blood was suggested to be a method of choice to detect MRD. We have studied 22 newly diagnosed childhood acute leukemias and 17 cases in remission. As controls, 19 patients with non-leukemic diseases were included. The majority of our acute leukemia cases (80%) were proved to be WT1 expressors using a highly sensitive nested PCR technique. Ten WT1 + cases have been monitored for a year throughout the inicial therapy phase, using peripheral blood tests. We observed that in 20% of the follow-up cases MRD was suggested which was not detectable by any other methods. It is our intention to introduce this new molecular technique into the clinical management of childhood acute leukemia.

[Detection of n-myc gene amplification in neuroblastoma using polymerase chain reaction based methods]. / N-myc-amplifikáció vizsgálata neuroblastomában PCR-alapú módszerekkel.

We have used semiquantitative and real-time quantitative PCRs to detect n-myc gene-amplification in 21 frozen neuroblastoma biopsies and IMR 32 cell line in order to predict biological behaviour of the tumors. Two primer pairs were used in the semiquantitative method to co-amplify a 520-bp fragment of the beta -globin gene -used as a single copy reference standard -and a 258-bp fragment of the n-myc gene. After 30 cycles the PCR products were electrophoresed through an agarose gel and were compared to each other with use of a gel-densitometer. Real-time quantitative analysis was performed in a LightCycler instrument. A single primer pair was used to amplify a 120-bp fragment of the n-myc oncogene and a LC640-labelled fluorescent probe pair to detect the product. Calibration curve, which was set up from a serial dilution including samples with 1, 2, 10, 13, 25-fold n-myc oncogene amplification, was employed for quantitative analysis. Semiquantitative method did not show distinct difference between tumor groups with no amplification and less than 10-fold amplification, while quantitative LightCycler analysis was able to detect even 2-fold amplification. In situ PCRs were performed in two cases of differentiated tumor samples which contained n-myc amplification. We used biotinylated ATP labelling and the same primer pair as for the LightCycler analysis.In both cases differentiated cell forms did not show n-myc gene amplification, while considerable amplification was detected in the neuroblasts.

[Experiences with Langerhans' cell histiocytosis in children in Hungary]. / Gyermekkori Langerhans-sejtes histiocytosissal szerzett magyarországi tapasztalataink.

BACKGROUND: Langerhans cell histiocytosis (LCH) in children is relatively rare, and the long-term analysis of therapy results has not been done yet in Hungary. PURPOSE: In this review we summarise the incidence, clinical features, prognostic risk factors and treatment results of children's LCH in Hungary, using data from the National Childhood Cancer Registry in Hungary in a 20-year period between 1981 and 2000. RESULTS: From January 1981 to December 2000, 111 children under 18 years of age were newly diagnosed with LCH in Hungary. The male-female ratio was 1.36:1, the mean age: 4 years 11 months. The minimal and median follow-up time was 3.48 years and 10.98 years respectively. 38 children had single-system disease, while in 73 cases we found systemic dissemination already at the time of diagnosis. Twenty-two patients were treated only by local surgery, 7 by surgery with local irradiation and 5 children received only local irradiation. In two cases remission was obtained with local steroid administration. 75 patient received chemotherapy. During the twenty years 14 children died, 9 due to the progression of the disease. Sixteen of the 111 patients had relapse with a mean of 2.16+/-1.29 years after the first diagnosis. Three patients with relapse got chemotherapy generally used in lymphoma and remission was achieved. The overall survival of all patients (n=111) was 88.3+/-3.1% at 5 years and 87.3+/-3.2% at 10 and 20 years. CONCLUSION: Childhood LCH is a well treatable disease and the survival rate is high. Even disseminated diseases have a quite good prognosis in childhood.

Intensive chemotherapy for childhood acute lymphoblastic leukemia: results of the randomized intercontinental trial ALL IC-BFM 2002.

PURPOSE: 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. PATIENTS AND METHODS: 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). RESULTS: 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. CONCLUSION: 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.

The role of ABC-transporter gene polymorphisms in chemotherapy induced immunosuppression, a retrospective study in childhood acute lymphoblastic leukaemia.

We examined the association of functional ABCB1 (MDR1) and ABCG2 (BCRP) polymorphisms with acute side effects of chemotherapy. Analyses were performed on clinical data from 138 patients treated with the ALL-BFM-95 protocol implying several substrates of these transporters. ABCB1 3435T>C, 2677G>T/A 1236C>T and ABCG2 421C>A genotypes were determined. A higher proportion of ABCB1 3435TT patients suffered excessive infectious complications than those harbouring at least one C allele (OR=2.5, p=0.03) during the whole half-year-long intensive phase of chemotherapy. Weaker associations were calculated when ABCB1 1236T-2677T-3435T haplotype homozygotes were tested against the remaining part of the population (OR=2.3, p=0.09). During the reinduction phase of therapy, the occurrence of severe leukocytopenia was similar among ABCB1 genotype groups. The frequency of any toxicities were not shown to differ according to the ABCG2 421C>A genotype. Our data suggest that the ABCB1 3435T>C genotype is associated with the infectious complications of the applied chemotherapy regimen.