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ALK positive diffuse large B-cell lymphomas (DLBCL) are a distinct lymphoma subtype associated with a poor outcome. Most of them feature a t(2;17) encoding a clathrin (CLTC)-ALK fusion protein. The contribution of deregulated ALK-activity in the pathogenesis and maintenance of these DLBCLs is not yet known. We established and characterized the first CLTC-ALK positive DLBCL cell line (LM1). LM1 formed tumors in NOD-SCID mice. The selective ALK inhibitor NVP-TAE684 inhibited growth of LM1 cells in vitro at nanomolar concentrations. NVP-TAE684 repressed ALK-activated signalling pathways and induced apoptosis of LM1 DLBCL cells. Inhibition of ALK-activity resulted in sustained tumor regression in the xenotransplant tumor model. These data indicate a role of CLTC-ALK in the maintenance of the malignant phenotype thereby providing a rationale therapeutic target for these otherwise refractory tumors.

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. 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/m 2 weekly for 2 weeks) and dexamethasone (6 mg/m 2 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. 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). 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.

With the aim of describing the long-term follow-up and to define the prognostic role of the clinical/pathological/molecular characteristics at diagnosis for childhood, adolescent and young adults affected by anaplastic large cell lymphoma (ALCL), we analyzed 420 patients aged up to 22 years homogeneously treated within the international ALCL99 trial. The 10-year progression free survival (PFS) was 70% and overall survival was 90%, rare late relapses occurred but no secondary malignancies were reported. Among clinical/pathological characteristics, only patients presenting a small cell/lymphohistiocytic (SC/LH) pattern were independently associated with risk of failure (hazard ratio = 2.49). Analysis of minimal disseminated disease (MDD), available for 162 patients, showed that both SC/LH pattern (hazard ratio = 2.4) and MDD positivity (hazard ratio = 2.15) were significantly associated with risk of failure in multivariate analysis. Considering MDD and SC/LH results, patients were separated into three biological/pathological (bp) risk groups: a high-risk group (bpHR) including MDD-positive patients with SC/LH pattern; a low-risk group (bpLR) including MDD-negative patients without SC/LH pattern; and an intermediate-risk group (bpIR) including remaining patients. The 10-year PFS was 40%, 75% and 86% for bpHR, bpIR and bpLR, respectively (p < 0.0001). These results should be considered in the design of future ALCL trials to tailor individual treatments.

Data on clinical features and outcome in pediatric follicular lymphoma (pFL) are scarce. The aim of this retrospective study including 13 EICNHL and/or i-BFM study group members was to assess clinical characteristics and course in a series of 63 pFL patients. pFL was found to be associated with male gender (3:1), older age (72 % ≥10 years old), low serum LDH levels (<500 U/l in 75 %), grade 3 histology (in 88 %), and limited disease (87 % stage I/II disease), mostly involving the peripheral lymph nodes. Forty-four out of sixty-three patients received any polychemotherapy and 1/63 rituximab only, while 17/63 underwent a “watch and wait” strategy. Of 36 stage I patients, 30 had complete resections. Only one patient relapsed; 2-year event-free survival and overall survival were 94 ± 5 and 100 %, respectively, after a median follow-up of 2.2 years. Conclusively, treatment outcome in pFL seems to be excellent with risk-adapted chemotherapy or after complete resection and an observational strategy only.

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. 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 100×10 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. 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). 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.

Recent studies in adult lymphoma patients have indicated a correlation between polymorphisms of Fc gamma-receptors (FcγRs, encoded by the respective FCGR genes) and the response to rituximab treatment. In vitro, cells expressing FcγRIIIa-158V mediate antibody-dependent cellular cytotoxicity (ADCC) more efficiently than cells expressing FcγRIIIa-158F. The impact of the FCGR2A-131HR polymorphism is unclear. In this study, the FCGR polymorphisms FCGR3A-158VF and FCGR2A-131HR were analyzed in pediatric patients with mature aggressive B cell non-Hodgkin lymphoma/leukemia (B-NHL). Pediatric patients received a single dose of rituximab monotherapy. Response was evaluated on day 5 followed by standard chemotherapy for B-NHL. Among 105 evaluable patients, a response to rituximab was observed in 21 % of those homozygous for FcγRIIa-131RR (5/24) compared to 48 % of patients who were HH and HR FcγRIIa-131 allele carriers (18/34 and 21/47, respectively; p  = 0.044). Among patients with the FCGR3A-158 polymorphism, those homozygous for the FF genotype had a significantly favorable rituximab response rate of 59 % (22/37) compared to 32 % in patients who were FcγRIIIa-158VV and FcγRIIIa-VF allele carriers (2/9 and 20/59, respectively; p  = 0.022). A stringent phase II response evaluation of children and adolescents with B-NHL after one dose of rituximab monotherapy showed a significant association between the rituximab response rate and FCGR polymorphisms. These findings support the hypothesis that FCGR polymorphisms represent patient-specific parameters that influence the response to rituximab.

To evaluate the clinical benefit of the prophylactic use of urate oxidase in children with non-Hodgkin's lymphoma (NHL), we analyzed the incidence and complications of tumor lysis syndrome (TLS) in children with B-cell acute lymphoblastic leukemia (B-ALL) or stage III/IV Burkitt's lymphoma and a lactate dehydrogenase (LDH) level > or =500 U/l before and after the introduction of a protocol amendment to use urate oxidase for the prophylaxis of TLS. Data from 1791 children with NHL enrolled in the two subsequent multicenter studies NHL-BFM 90 and 95 were evaluated. The presence of the side effects TLS, anuria, sepsis, and other complications during the first 2 weeks after admission were registered. Until March 1996, no urate oxidase was used (period 1). From November 1997 all children with B-ALL or stage III and IV B-NHL and LDH > or =500 U/l should receive urate oxidase prophylactically (period 3). In between (period 2), urate oxidase was given in a minority of hospitals therapeutically. Initial chemotherapy was identical. Altogether, 78 children (4.4%) developed a TLS. Patients with B-ALL had the highest risk to develop a TLS (26.4%) followed by B-ALL/Burkitt's lymphoma and a LDH > or =500 U/l (14.9%). In period 1, 16.1% and 9.2% of the latter children developed a TLS or anuria, respectively, compared to 12.3% and 6.2% in period 3 ( p=NS). The incidence of sepsis remained unchanged (5.0% vs 4.6%). In children with B-ALL the differences in the incidence of TLS and anuria between period 3 and period 1 were more pronounced, reaching significance for anuria (15.4% vs 3.8%, p=0.03). Our results suggest that patients with the highest risk to develop a TLS might benefit from the prophylactic use of urate oxidase.

We analyzed the relationship of genetic variation within the methylenetetrahydrofolate reductase gene (MTHFR 677 C-->T) with clinical characteristics, outcome, and therapy-related toxicity in pediatric non-Hodgkin's lymphoma (NHL) in our multicenter trial NHL-BFM 95. In this trial, high-dose methotrexate (MTX) infusion regimens were randomized (4- vs 24-h infusion) in patients with B-cell lymphoma; MTX was applied as 24-h infusion in all patients with lymphoblastic lymphoma and anaplastic large cell lymphoma. Toxicity data were collected per patient and therapy course according to National Cancer Institute Common Toxicity Criteria (NCI-CTC). The genotypes in 484 pediatric patients were distributed as follows: MTHFR 677 CC, 206 patients (42.6%); MTHFR 677 CT, 214 patients (44.2%); and MTHFR 677 TT, 64 patients (13.2%). Lymphoblastic lymphoma was significantly associated with homozygosity for the MTHFR 677 T allele. No association of MTHFR 677 genotype with clinical characteristics (sex, age, and tumor stage), outcome, or therapy-related toxicity could be detected. Therefore, we conclude that the MTHFR 677 C-->T polymorphism does not appear to influence outcome or therapy-associated toxicity in pediatric patients with NHL treated on BFM protocols.

ALK positive diffuse large B-cell lymphomas (DLBCL) are a distinct lymphoma subtype associated with a poor outcome. Most of them feature a t(2;17) encoding a clathrin (CLTC)-ALK fusion protein. The contribution of deregulated ALK-activity in the pathogenesis and maintenance of these DLBCLs is not yet known. We established and characterized the first CLTC-ALK positive DLBCL cell line (LM1). LM1 formed tumors in NOD-SCID mice. The selective ALK inhibitor NVP-TAE684 inhibited growth of LM1 cells in vitro at nanomolar concentrations. NVP-TAE684 repressed ALK-activated signalling pathways and induced apoptosis of LM1 DLBCL cells. Inhibition of ALK-activity resulted in sustained tumor regression in the xenotransplant tumor model. These data indicate a role of CLTC-ALK in the maintenance of the malignant phenotype thereby providing a rationale therapeutic target for these otherwise refractory tumors.