Summary Background Gemtuzumab Ozogamicin (GO) was the first example of antibody directed chemotherapy in cancer and developed for Acute Myeloid Leukaemia. Its role has been unclear. Five randomised trials where it was combined with standard induction chemotherapy in adults have produced different results. In an effort to clarify the level of benefit, if any, and in which patients outcomes might be improved, an individual patient data meta-analysis of these 5 trials has been undertaken. Methods All randomised trials of GO in adults (age >15), given in conjunction with the first course of intensive induction chemotherapy for AML (excluding APL) were identified. In a collaboration between the groups involved, source data concerning demographics, treatment was requested in May 2013 and collected in 3325 randomised patients (median age 58). All trials were centrally randomised and open-label, with survival as primary endpoint. Analyses are presented by standard techniques, and within standardised risk groups Results Remission rates were not increased, but by significantly reducing the risk of relapse overall survival at 5 years was improved irrespective of patient age (30.7% vs 34.6%; HR 0.90 (95% CI 0.82-0.98), p=0.01). The survival benefit was particularly clear in those with favourable cytogenetics (55.2% vs 76.3%; HR0.47 (0.31-0.73), p=0.0005), but also observed in intermediate risk patients (34.1% vs 39.4%; HR 0.84 (0.75-0.95), p=0.007) Patients with adverse karyotype did not benefit overall or within any trial. Dose levels of 3mg/m2 were associated with less toxicity and equal efficacy. Interpretation GO can be safely added to conventional induction therapy. For patients who do not have adverse cytogenetics there is a significant survival benefit. These data suggest that the use of GO should be re-evaluated and the license status of GO may need to be reviewed. Role of funding source There was no funder for this meta-analysis.

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Key Points• Integrating cytogenetic and genomic data in pediatric ALL reveals 2 subgroups with different outcomes independent of other risk factors.• A total of 75% of children on UKALL2003 had a good-risk genetic profile, which predicted an EFS and OS of 94% and 97% at 5 years.

JAK signaling pathway members in 27.7% of T-ALL samples screened; an observation with therapeutic potential. Statistically significant pairwise associations were found between different mutations, indicating the presence of functional interactions among different pathways in T-ALL pathogenesis. Of significance, we found a mutually exclusive relationship between IL7R-JAK mutations and the presence of TAL1/LMO2 rearrangements. We also identified positive correlations among IL7R-JAK mutations and mutations/deletions in PHF6 and members of the PRC2 complex. Our findings begin to unravel the diversity of genetic lesions that are implicated in the development of T-ALL. Methods DNA samplesT-ALL samples from patients (n=155: 111 children, 44 adults) were collected from various institutions (Online Supplementary Table S1). The diagnosis of T-ALL was based on morphology, cytochemistry and immunophenotyping according to World Health Organization criteria. Genomic DNA was isolated from bone marrow (either fixed or fresh bone marrow cells). 5,21,22 To investigate the prognostic relevance of IL7R, JAK1 and JAK3 mutations, Sanger sequencing was used to screen for mutations in these three genes in an independent cohort of 78 T-ALL patients. Those patients were all enrolled into the United Kingdom (UK) Children's Cancer and Leukaemia Group (CCLG) ALL2003 trial. 23This study was approved by the ethics committees of the institutes involved and informed consent was obtained from the participants. Samples and clinical data were stored in accordance with the declaration of Helsinki. Capture designSureDesign software was used to design two slightly different Haloplex capture assays (Table 1). The total amplicon number for design A was 23,127 with a region size of 472.006 kbp and a predicted target coverage of >99%. For design B the total amplicon number was 19,694 with a region size of 418.373 kbp and a predicted target coverage of >99%. For this study, 80 samples were processed with design A and 75 samples with design B. In both assays, the coding exons of selected genes (based on RefSeq, CCDS and VEGA databases) were targeted with an extra ten bases upstream and downstream. Targeted regions comprised the coding sequence of genes that were either recently identified as recurrently mutated in ALL or other hematologic malignancies (known driver genes) or were similar to known oncogenes (candidate driver genes) to be sequenced. 18,19,24,25 For statistical analyses we only considered the 115 genes that were sequenced in both Haloplex designs (Online Supplementary Table S2). Library preparation and sequencing were performed as described in the Online Supplementary Material. Data analysesIn NextGENe software (v2.2.1, Softgenetics, State College, PA, USA), we performed the following steps: (i) the fastQ output file was converted into a FASTA file to eliminate reads that were not "paired" and that did not meet the criteria of the default settings; (ii) reads from the converted unique FASTA file were aligned to the reference genome (...

Chromosomal abnormalities are increasingly used to risk stratify adults with acute lymphoblastic leukemia. Published data describing the age-specific incidence of chromosomal abnormalities and their prognostic relevance are largely derived from clinical trials. Trials frequently have age restrictions and low recruitment rates. Thus we investigated these factors in a population-based cohort of 349 patients diagnosed during the course of 19 years in the northern part of England. The incidence of most chromosomal abnormalities varied significantly with age.The incidence of t(9;22)(q34;q11) increased in each successive decade, up to 24% among 40-to 49-year-old subjects. Thereafter the incidence reached a plateau. t(4;11)(q21;q23) and t(1;19)(q23; p13) were a rare occurrence among patients older than 60 years of age. In contrast, the frequency of t(8;14)(q24;q32) and t(14;18)(q32;q21) increased with age. High hyperdiploidy occurred in 13% of patients younger than 20 years of age but in only 5% of older patients. The incidence of low hypodiploidy/near-triploidy and complex karyotype increased with age from 4% (15-29 years) to 16% (> 60 years). Overall survival varied significantly by age and cytogenetics. Older patients and those with t(9;22), t(4;11), low hypodiploidy/near-triploidy, or complex karyotype had a significantly inferior outcome. These population-based results demonstrate the cytogenetic heterogeneity of adult acute lymphoblastic leukemia. These data will inform the delivery of routine clinical services and the design of new age-focused clinical trials. (Blood. 2010;115:206-214)