Noncoding mutations drive persistence of a founder preleukemic clone which initiates late relapse in T-ALL.

ABSTRACT: T-ALL relapse usually occurs early but can occur much later, which has been suggested to represent a de novo leukemia. However, we conclusively demonstrate late relapse can evolve from a pre-leukemic subclone harbouring a non-coding mutation that evades initial chemotherapy.

Very early lineage-specific chimerism after reduced intensity stem cell transplantation is highly predictive of clinical outcome for patients with myeloid disease.

BACKGROUND: The importance of chimerism status in the very early period after hematopoietic stem cell transplantation is unclear. We determined PBMC and T-cell donor chimerism 50 days after transplantation and related this to disease relapse and overall survival. METHODS: 144 sequential patients underwent transplantation of which 90 had AML/MDS and 54 had lymphoma. 'Full donor chimerism' was defined as ≥99% donor cells and three patient groups were defined: 40% with full donor chimerism (FC) in both PBMC and T-cells; 25% with mixed chimerism (MC) within both compartments and 35% with 'split' chimerism (SC) characterised by full donor chimerism within PBMC and mixed chimerism within T-cells. RESULTS: In patients with myeloid disease a pattern of mixed chimerism (MC) was associated with a one year relapse rate of 45% and a five year overall survival of 40% compared to values of 8% and 75%, and 17% and 60%, for those with SC or FC respectively. The pattern of chimerism had no impact on clinical outcome for lymphoma. CONCLUSION: The pattern of lineage-specific chimerism at 50 days after transplantation is highly predictive of clinical outcome for patients with myeloid malignancy and may help to guide subsequent clinical management.

Assessment of Minimal Residual Disease in Standard-Risk AML.

BACKGROUND: Despite the molecular heterogeneity of standard-risk acute myeloid leukemia (AML), treatment decisions are based on a limited number of molecular genetic markers and morphology-based assessment of remission. Sensitive detection of a leukemia-specific marker (e.g., a mutation in the gene encoding nucleophosmin [NPM1]) could improve prognostication by identifying submicroscopic disease during remission. METHODS: We used a reverse-transcriptase quantitative polymerase-chain-reaction assay to detect minimal residual disease in 2569 samples obtained from 346 patients with NPM1-mutated AML who had undergone intensive treatment in the National Cancer Research Institute AML17 trial. We used a custom 51-gene panel to perform targeted sequencing of 223 samples obtained at the time of diagnosis and 49 samples obtained at the time of relapse. Mutations associated with preleukemic clones were tracked by means of digital polymerase chain reaction. RESULTS: Molecular profiling highlighted the complexity of NPM1-mutated AML, with segregation of patients into more than 150 subgroups, thus precluding reliable outcome prediction. The determination of minimal-residual-disease status was more informative. Persistence of NPM1-mutated transcripts in blood was present in 15% of the patients after the second chemotherapy cycle and was associated with a greater risk of relapse after 3 years of follow-up than was an absence of such transcripts (82% vs. 30%; hazard ratio, 4.80; 95% confidence interval [CI], 2.95 to 7.80; P<0.001) and a lower rate of survival (24% vs. 75%; hazard ratio for death, 4.38; 95% CI, 2.57 to 7.47; P<0.001). The presence of minimal residual disease was the only independent prognostic factor for death in multivariate analysis (hazard ratio, 4.84; 95% CI, 2.57 to 9.15; P<0.001). These results were validated in an independent cohort. On sequential monitoring of minimal residual disease, relapse was reliably predicted by a rising level of NPM1-mutated transcripts. Although mutations associated with preleukemic clones remained detectable during ongoing remission after chemotherapy, NPM1 mutations were detected in 69 of 70 patients at the time of relapse and provided a better marker of disease status. CONCLUSIONS: The presence of minimal residual disease, as determined by quantitation of NPM1-mutated transcripts, provided powerful prognostic information independent of other risk factors. (Funded by Bloodwise and the National Institute for Health Research; Current Controlled Trials number, ISRCTN55675535.).

VHL mutation analysis in patients with isolated central nervous system haemangioblastoma.

Haemangioblastomas of the CNS are a cardinal feature of von Hippel-Lindau (VHL) disease, a dominantly inherited multisystem familial cancer syndrome caused by germline mutation of the VHL tumour suppressor gene. We investigated the frequency of VHL mutations in 188 patients presenting with a single haemangioblastoma, no family history of VHL disease and no evidence of retinal or abdominal manifestations of the disease at the time of diagnosis. We found that approximately 4% of patients had a detectable VHL mutation and all of these cases presented age 40 years or less. Although the identification of a germline VHL mutation has important consequences for the patient (e.g. risk of further CNS and extra-CNS tumours) and their relatives, four patients had germline VHL missense mutations [C162Y, D179N and R200W (two patients)] that may represent haemangioblastoma-only and/or low penetrance mutations. Approximately 5% of patients without a detectable VHL mutation subsequently developed a further 'VHL type tumour' (in most cases a further CNS haemangioblastoma). These findings suggest that a subset of patients with apparently sporadic CNS haemangioblastoma will have a germline VHL mutation but may not be at risk for developing classical VHL disease and a further group may be mosaic for a germline VHL mutation that cannot be detected in blood cells.