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Activating mutations in the NOTCH1 pathway are frequent in pediatric T-cell acute lymphoblastic leukemia (T-ALL) but their role in refining risk stratification is unclear. We screened 162 pediatric T-ALL patients treated on the MRC UKALL2003 trial for NOTCH1/FBXW7 gene mutations and related genotype to response to therapy and long-term outcome. Overall, 35% were wild-type (WT) for both genes (NOTCH1WTFBXW7WT), 38% single NOTCH1 mutant (NOTCH1SingleFBXW7WT), 3% just FBXW7 mutant (NOTCH1WTFBXW7MUT) and 24% either double NOTCH1 mutant (NOTCH1DoubleFBXW7WT) or mutant in both genes (NOTCH1MUTFBXW7MUT), hereafter called as NOTCH1±FBXW7Double. There was no difference between groups in early response to therapy, but NOTCH1±FBXW7Double patients were more likely to be associated with negative minimal residual disease (MRD) post-induction than NOTCH1WTFBXW7WT patients (71% versus 40%, P=0.004). Outcome improved according to the number of mutations, overall survival at 5 years 82%, 88% and 100% for NOTCH1WTFBXW7WT, NOTCH1SingleFBXW7WT and NOTCH1±FBXW7Double patients, respectively (log-rank P for trend=0.005). Although 14 NOTCH1±FBXW7Double patients were classified as high risk (slow response and/or MRD positive), only two had disease progression and all remain alive. Patients with double NOTCH1 and/or FBXW7 mutations have a very good outcome and should not be considered for more intensive therapy in first remission, even if slow early responders or MRD positive after induction therapy. [ABSTRACT FROM AUTHOR]

Assessment of minimal residual disease (MRD) has acquired a prominent position in European treatment protocols for patients with acute lymphoblastic leukemia (ALL), on the basis of its high prognostic value for predicting outcome and the possibilities for implementation of MRD diagnostics in treatment stratification. Therefore, there is an increasing need for standardization of methodologies and harmonization of terminology. For this purpose, a panel of representatives of all major European study groups on childhood and adult ALL and of international experts on PCR- and flow cytometry-based MRD assessment was built in the context of the Second International Symposium on MRD assessment in Kiel, Germany, 18–20 September 2008. The panel summarized the current state of MRD diagnostics in ALL and developed recommendations on the minimal technical requirements that should be fulfilled before implementation of MRD diagnostics into clinical trials. Finally, a common terminology for a standard description of MRD response and monitoring was established defining the terms ‘complete MRD response’, ‘MRD persistence’ and ‘MRD reappearance’. The proposed MRD terminology may allow a refined and standardized assessment of response to treatment in adult and childhood ALL, and provides a sound basis for the comparison of MRD results between different treatment protocols. [ABSTRACT FROM AUTHOR]

Leukemia (2003) 17, 247–251. doi:10.1038/sj.leu.2402759 [ABSTRACT FROM AUTHOR]

We have tested the hypothesis that functional dendritic cells (DC) may be generated from patients with acute lymphoblastic leukaemia (ALL). We evaluated the production of DC from blast cells taken at presentation from nine children with ALL. Blast cells were expanded in serum-free medium supplemented with Flt3L, G-CSF, GM-CSF, IL-3, IL-6 and SCF for 7 days and subsequently stimulated with Flt3L, GM-CSF and TGF-beta for a further 14 days, with the addition of TNF-alpha for the final 48 h of culture. Cultured cells had the morphological appearance of DC and expressed the DC-associated antigens CD1A (range 2-87%) and CD83 (15-44%). Expression of the co-stimulatory molecules CD80 and CD86 was increased and the majority of these cells retained their expression of CD34 (73+/-4%) and HLA-DR (79+/-5%). Seven of the nine ALL had a leukaemia-specific abnormality and DC generated from five of these seven cases were derived from the leukaemic clone. Leukaemic DC derived from four HLA-A*02-positive ALL pulsed with CMV-associated peptides could induce significant proliferation of peptide-specific CD8+ T cells. This specificity was verified using tetrameric complexes of HLA class l/antigenic peptide. DC could also be generated from cells taken at times of complete remission of ALL and from normal controls using these culture conditions. These findings show that functional DC can be generated both from ALL blasts and from patients in remission; these might be utilised in future for immunotherapeutic strategies in the treatment of ALL. [ABSTRACT FROM AUTHOR]

This article discusses research on the clinical spectrum of intrathecal methotrexate (IT MTX)-related stroke-like syndrome (SLS) in patients with acute lymphoblastic leukaemia (ALL) who were treated during the Medical Research Council UKALL 2003 trial in Great Britain. Researchers reviewed 203 investigator-generated reports of neurological serious adverse effects associated with IT MTX administration and learned that 31 cases are consistent with an SLS-type presentation.

Leukemia (2003) 17, 268–270. doi:10.1038/sj.leu.2402751 [ABSTRACT FROM AUTHOR]