Key Points• CMV serostatus significantly influences chimerism levels after T-cell-depleted allogeneic transplantation.• CMV-specific T cells are exclusively of recipient origin after R1/D2 T-cell-depleted transplants and appear to provide protective immunity.Cytomegalovirus (CMV) remains a significant cause of morbidity after allogeneic hematopoietic stem cell transplantation (HSCT). Clinical risk varies according to a number of factors, including recipient/donor CMV serostatus. Current dogma suggests risk is greatest in seropositive recipient (R1)/seronegative donor (D2) transplants and is exacerbated by T-cell depletion. We hypothesized that in the setting of reduced-intensity T-celldepleted conditioning, recipient-derived CMV-specific T cells escaping deletion may contribute significantly to CMV-specific immunity and might therefore also influence chimerism status. We evaluated 105 recipients of alemtuzumab-based reduced-intensity HSCT and collated details on CMV infection episodes and T-cell chimerism. We used CMV-specific HLA multimers to enumerate CMV-specific T-cell numbers and select cells to assess chimerism status in a subset of R1/D2 and R1/seropositive donor patients. We show that in R1/D2 patients, CMV-specific T cells are exclusively of recipient origin, can protect against recurrent CMV infections, and significantly influence the chimerism status toward recipients. The major findings were replicated in a separate validation cohort. T-cell depletion in the R1/D2 setting may actually, therefore, foster more rapid reconstitution of protective antiviral immunity by reducing graft-vs-host directed alloreactivity and the associated elimination of the recipient T-cell compartment. Finally, conversion to donor chimerism after donor lymphocytes is associated with clinically occult transition to donor-derived immunity. (Blood. 2015;125(4):731-739)
Modern management of acute myeloid leukaemia (AML) relies on the integration of phenotypic and genetic data to assign classification, establish prognosis, enhance monitoring and guide treatment. The prism through which we can now disperse a patient's leukaemia, interpret and apply our understanding has fundamentally changed since the completion of the first whole-genome sequencing (WGS) of an AML patient in 2008 and where possible, many clinicians would now prefer to delay treatment decisions until the karyotype and genetic status of a new patient is known. The success of global sequencing initiatives such as The Cancer Genome Atlas (TCGA) have brought us significantly closer to cataloguing the full spectrum of coding mutations involved in human malignancy. Indeed, genetic capability has raced ahead of our capacity to apply much of this knowledge into clinical practice and we are in the peculiar position of having routine access to genetic information on an individual patient's leukaemia that cannot be reliably interpreted or utilised. This is a measure of how rapid the progress has been, and this rate of change is likely to continue into the foreseeable future as research intensifies on the noncoding genome and the epigenome, as we scrutinise disease at a single cell level, and as initiatives like Beat AML and the Harmony Alliance progress. In this review, we will examine how interrogation of the coding genome is revolutionising our understanding of AML and improving our ability to underscore differences between paediatric and adult onset, sporadic and inherited forms of disease. We will look at how this knowledge is informing improvements in outcome prediction and the development of novel treatments, bringing us a step closer to personalised therapy for myeloid malignancy.
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