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We analyzed the long-term outcome of 4865 patients treated in Studies 82, 87, 88, 91 and 95 for childhood acute lymphoblastic leukemia (ALL) of the Italian Association of Pediatric Hematology and Oncology (AIEOP). Treatment was characterized by progressive intensification of systemic therapy and reduction of cranial radiotherapy. A progressive improvement of results with reduction of isolated central nervous system relapse rate was obtained. Ten-year event-free survival increased from 53% in Study 82 to 72% in Study 95, whereas survival improved from 64 to 82%. Since 1991, all patients were treated according to Berlin-Frankfurt-Muenster (BFM) ALL treatment strategy. In Study 91, reduced treatment intensity (25%) yielded inferior results, but intensification of maintenance with high-dose (HD)-L-asparaginase (randomized) allowed to compensate for this disadvantage; in high-risk patients (HR, 15%), substitution of intensive polychemotherapy blocks for conventional BFM backbone failed to improve results. A marked improvement of results was obtained in HR patients when conventional BFM therapy was intensified with three polychemotherapy blocks and double delayed intensification (Study 95). The introduction of minimal residual disease monitoring and evaluation of common randomized questions by AIEOP and BFM groups in the protocol AIEOP-BFM-ALL 2000 are expected to further ameliorate treatment of children with ALL. [ABSTRACT FROM AUTHOR]

An international childhood acute lymphoblastic leukemia (ALL)working group was formed during the 27th annual meeting of the International Society of Pediatric Oncology in 1995. Since then, 10 workshops have been held to address many issues that help advance treatment outcome of childhood ALL but require international collaboration (Table 1). The group was fondly named after 'Ponte di Legno,' a place in Lombardy, Italy, because the first major workshop was held there. In celebration of the 10th anniversary of the first major meeting, the group returned to Ponte di Legno on 6 and 7 May 2009 for its 11th meeting (Figure 1). During the meeting, Professor Giuseppe Masera was honored for his vision and contributions to further develop the International-BFM study group and to co-found the Ponte di Legno working group. The meeting began with greetings by Professor Andrea Biondi. This report summarizes the data presented and the discussion in the meeting. [ABSTRACT FROM AUTHOR]

Detection of minimal residual disease (MRD) is the most sensitive method to evaluate treatment response and one of the strongest predictors of outcome in childhood acute lymphoblastic leukemia (ALL). The 10-year update on the I-BFM-SG MRD study 91 demonstrates stable results (event-free survival), that is, standard risk group (MRD-SR) 93%, intermediate risk group (MRD-IR) 74%, and high risk group (MRD-HR) 16%. In multicenter trial AIEOP-BFM ALL 2000, patients were stratified by MRD detection using quantitative PCR after induction (TP1) and consolidation treatment (TP2). From 1 July 2000 to 31 October 2004, PCR target identification was performed in 3341 patients: 2365 (71%) patients had two or more sensitive targets (10−4), 671 (20%) patients revealed only one sensitive target, 217 (6%) patients had targets with lower sensitivity, and 88 (3%) patients had no targets. MRD-based risk group assignment was feasible in 2594 (78%) patients: 40% were classified as MRD-SR (two sensitive targets, MRD negativity at both time points), 8% as MRD-HR (MRD 10−3 at TP2), and 52% as MRD-IR. The remaining 823 patients were stratified according to clinical risk features: HR (n=108) and IR (n=715). In conclusion, MRD-PCR-based stratification using stringent criteria is feasible in almost 80% of patients in an international multicenter trial.Leukemia (2008) 22, 771–782; doi:10.1038/leu.2008.5; published online 31 January 2008 [ABSTRACT FROM AUTHOR]

Minimal residual disease (MRD) diagnostics is used for treatment stratification in childhood acute lymphoblastic leukemia. We aimed to identify and solve potential problems in multicenter MRD studies to achieve and maintain consistent results between the AIEOP/BFM ALL-2000 MRD laboratories. As the dot-blot hybridization method was replaced by the real-time quantitative polymerase chain reaction (RQ-PCR) method during the treatment protocol, special attention was given to the comparison of MRD data obtained by both methods and to the reproducibility of RQ-PCR data. Evaluation of all key steps in molecular MRD diagnostics identified several pitfalls that resulted in discordant MRD results. In particular, guidelines for RQ-PCR data interpretation appeared to be crucial for obtaining concordant MRD results. The experimental variation of the RQ-PCR was generally less than three-fold, but logically became larger at low MRD levels below the reproducible sensitivity of the assay (<10−4). Finally, MRD data obtained by dot-blot hybridization were comparable to those obtained by RQ-PCR analysis (r2=0.74). In conclusion, MRD diagnostics using RQ-PCR analysis of immunoglobulin/T-cell receptor gene rearrangements is feasible in multicenter studies but requires standardization; particularly strict guidelines for interpretation of RQ-PCR data are required. We further recommend regular quality control for laboratories performing MRD diagnostics in international treatment protocols.Leukemia (2007) 21, 706–713. doi:10.1038/sj.leu.2404535; published online 8 February 2007 [ABSTRACT FROM AUTHOR]

The International Acute Lymphoblastic Leukemia Working Group, the so-called ‘Ponte di Legno Workshop’ has led to substantial progress in international collaboration in leukemia research. On April 27–28, 2005, the 8th Meeting was held in Vienna, Austria, to continue the discussions about special common treatment elements in randomized clinical trials, ethical and clinical aspects of therapy. Furthermore, collaborative projects of clinical relevance with special emphasis on rare genetic subtypes of Childhood ALL were established. The following report summarizes the achievements and aspects of possible future cooperation.Leukemia (2006) 20, 9–17. doi:10.1038/sj.leu.2404016; published online 10 November 2005 [ABSTRACT FROM AUTHOR]

Between 1995 and 2004, six International Childhood Acute Lymphoblastic Leukemia (ALL) Workshop have been held, and the completion of several collaborative projects has established the clinical relevance and treatment options for several specific genetic subtypes of ALL. This meeting report summarizes the data presented in the seventh meeting and the discussion.Leukemia (2005) 19, 1145–1152. doi:10.1038/sj.leu.2403783 Published online 5 May 2005 [ABSTRACT FROM AUTHOR]

The Sixth International Childhood ALL Workshop was made possible by unrestricted educational grants from Sanofi-Synethelabo Inc., Glaxosmithkline, Enzon Inc., and Ilex. Preparation of the Meeting Report was supported in part by the Österreichische Kinderkrebshilfe and private donations to the Children's Cancer Research Institute; the Associazione Italiana Ricerca sul Cancro, Fondazione Tettamanti, and Consiglio Nazionale Ricerche-Ministero Instruzione Universitá Ricerca); the Deutsche Krebshilfe, Bonn, and Madeleine Schickedanz Foundation, Fürth, Germany; Cancer Research UKJ; grants from the US National Institutes of Health (CA-21765, CA-51001, CA-31566, CA-78824, CA-29139, CA-37379, GM-61393, and GM61374), a Center of Excellence grant from the State of Tennessee, and the American Lebanese Syrian Associated Charities (ALSAC). C-H Pui is the American Cancer Society - FM Kirby Clinical Research Professor.Leukemia (2004) 18, 1043-1053. doi:10.1038/sj.leu.2403365 Published online 15 April 2004 [ABSTRACT FROM AUTHOR]

Reports that gene expression profile reveals significant differences between childhood and adult Ph+ acute lymphoblastic leukemia (ALL). Percentage of children suffering from ALL being identified with translocation; Considerations on which diagnosis of ALL Ph+ in clinical settings was based; Comparison of gene expression profile for prednisone good response and prednisone poor response pediatric patients.

To assess the clinical heterogeneity among patients with acute lymphoblastic leukemia (ALL) and various 11q23 abnormalities, we analyzed data on 497 infants, children and young adults treated between 1983 and 1995 by 11 cooperative groups and single institutions. The substantial sample size allowed separate analyses according to age younger or older than 12 months for the various cytogenetic subsets. Infants with t(4;11) ALL had an especially dismal prognosis when their disease was characterized by a poor early response to prednisone (P=0.0005 for overall comparison; 5-year event-free survival (EFS), 0 vs 23 ± 12% s.e. for those with good response), or age less than 3 months (P=0.0003, 5-year EFS, 5 ± 5% vs 23.4 ± 4% for those over 3 months). A poor prednisone response also appeared to confer a worse outcome for older children with t(4;11) ALL. Hematopoietic stem cell transplantation failed to improve outcome in either age group. Among patients with t(11;19) ALL, those with a T-lineage immunophenotype, who were all over I year of age, had a better outcome than patients over I year of age with B-lineage ALL (overall comparison, P=0.065; 5-year EFS, 88 ± 13 vs 46 ± 14%). In the heterogeneous subgroup with del(11)(q23), National Cancer Institute-Rome risk criteria based on age and leukocyte count had prognostic significance (P=0.04 for overall comparison; 5-year EFS, 64 ± 8% (high risk) vs 83 ± 6% (standard risk)). This study illustrates the marked clinical heterogeneity among and within subgroups of infants or older children with ALL and specific 11q23 abnormalities, and identifies patients at particularly high risk of failure who may benefit from innovative therapy. [ABSTRACT FROM AUTHOR]

Leukemia (2003) 17, 798-803. doi:10.1038/sj.leu.2402872 [ABSTRACT FROM AUTHOR]

Focuses on studies regarding childhood acute lymphoblastic leukemia (ALL). Cure rate of the disease; Description of diagnosis of patients with Philadelphia chromosome-positive ALL; Contribution of international collaborations to facilitate further treatment advances.

The first multicentric approach to childhood acute lymphoblastic leukemia (ALL) treatment in Italy started in the early 1970s when the Associazione Italiana di Ematologia ed Oncologia Pediatrica (AIEOP) was founded. Since then the AIEOP has conducted nationwide chemotherapy protocols. Results obtained in three different periods (1982-1986, 1987-1990, 1991-1995) are reported here. Treatment schedules have been characterized by a progressive intensification of systemic therapy and by a progressive substitution of protracted intrathecal therapy for cranial irradiation as central nervous system (CNS) preventive therapy. In the third period cranial radiotherapy (CRT) has been administered only to patients at high risk of relapse or with CNS involvement at diagnosis (about 15% of the overall population). A progressive improvement of therapeutic results, with a steady reduction of isolated CNS relapse rates have been obtained in the three periods considered here. The AIEOP experience shows that CRT can be safely omitted in non-high risk patients, unless they are T-ALL patients with WBC count at the diagnosis > or =100,000/mm3, and that intensification of treatment allows the improvement of overall results with a reduction of the impact of NCI prognostic criteria. Over the years, AIEOP has also continued to foster active cooperation at an international level. In the ongoing AIEOP ALL 2000 study, conducted in cooperation with the BFM group, patients are stratified according to the presence of translocations t(9;22) and t(4;11) and to treatment response (either initial steroid therapy or induction) or minimal residual disease). This cooperation will allow an adequate recruitment of patients to answer relevant randomized questions in the context of a study in which patients are stratified according to minimal residual disease findings. [ABSTRACT FROM AUTHOR]

Although most relapses of childhood acute lymphoblastic leukemia (ALL) occur 24-36 months after first CR has been achieved, few patients relapse 5 or more years after CR achievement. The assessment of clonality has proved to be useful in determining whether even those very late events represent the reoccurrence of the original clone or alternatively a secondary leukemia. To gain further information on clonal stability in such late relapse, we performed detailed comparative Southern blotting and PCR analyses of TcRδ and TcRγ gene rearrangements in five ALL at presentation and subsequent relapse which occurred more than 5 years after diagnosis. At least one stable rearranged allele of the TcRδ and TcRγ loci was traced in all cases at presentation and clinical relapse despite a wide heterogeneity of the pattern of rearrangements. Our study extends to a laRγer series of patients previous findings which have sought to analyze the phenomenon of clonal evolution in children relapsed after more than 5 years of CCR. With respect to the potential pitfalls in monitoring minimal residual disease in childhood ALL for the presence of clonal evolution, our results highlight the combination of two taRγet genes (such as TcRγ and TcRδ) as a tool to reduce false negative MR&DELTA; results. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented that discusses detection of PICALM-MLLT10 in children with T-lineage acute lymphoblastic leukemia.

The article focuses on professor Haig Riehm's contribution in making childhood acute lymphoblastic leukemia (ALL) a highly curable disease. A new regimen for treating childhood was developed by Riehm. An 8-week, 8-drug induction/consolidation regimen was developed by him and reasoned that it was critical to use multiple agents early in treatment. According to Riehm, the induction would improve the outcome by eliminating residual drug-resistant cells.

Focuses on the long-term results of large prospective clinical trials for treatment of acute lymphoblastic leukemia in children. Definition of patient groups for risk-adapted therapy; Workshops relating to childhood acute lymphoblastic leukemia held in various parts of the world.