Donor monocyte-derived macrophages promote human acute graft-versus-host disease.

Myelopoiesis is invariably present and contributes to pathology in animal models of graft-versus-host disease (GVHD). In humans, a rich inflammatory infiltrate bearing macrophage markers has also been described in histological studies. In order to determine the origin, functional properties, and role in pathogenesis of these cells, we isolated single-cell suspensions from acute cutaneous GVHD and subjected them to genotype, transcriptome, and in vitro functional analysis. A donor-derived population of CD11c+CD14+ cells was the dominant population of all leukocytes in GVHD. Surface phenotype and NanoString gene expression profiling indicated the closest steady-state counterpart of these cells to be monocyte-derived macrophages. In GVHD, however, there was upregulation of monocyte antigens SIRPα and S100A8/9 transcripts associated with leukocyte trafficking, pattern recognition, antigen presentation, and costimulation. Isolated GVHD macrophages stimulated greater proliferation and activation of allogeneic T cells and secreted higher levels of inflammatory cytokines than their steady-state counterparts. In HLA-matched mixed leukocyte reactions, we also observed differentiation of activated macrophages with a similar phenotype. These exhibited cytopathicity to a keratinocyte cell line and mediated pathological damage to skin explants independently of T cells. Together, these results define the origin, functional properties, and potential pathogenic roles of human GVHD macrophages.

Molecular MRD status and outcome after transplantation in NPM1-mutated AML.

Relapse remains the most common cause of treatment failure for patients with acute myeloid leukemia (AML) who undergo allogeneic stem cell transplantation (alloSCT), and carries a grave prognosis. Multiple studies have identified the presence of measurable residual disease (MRD) assessed by flow cytometry before alloSCT as a strong predictor of relapse, but it is not clear how these findings apply to patients who test positive in molecular MRD assays, which have far greater sensitivity. We analyzed pretransplant blood and bone marrow samples by reverse-transcription polymerase chain reaction in 107 patients with NPM1-mutant AML enrolled in the UK National Cancer Research Institute AML17 study. After a median follow-up of 4.9 years, patients with negative, low (<200 copies per 105ABL in the peripheral blood and <1000 copies in the bone marrow aspirate), and high levels of MRD had an estimated 2-year overall survival (2y-OS) of 83%, 63%, and 13%, respectively (P < .0001). Focusing on patients with low-level MRD before alloSCT, those with FLT3 internal tandem duplications(ITDs) had significantly poorer outcome (hazard ratio [HR], 6.14; P = .01). Combining these variables was highly prognostic, dividing patients into 2 groups with 2y-OS of 17% and 82% (HR, 13.2; P < .0001). T-depletion was associated with significantly reduced survival both in the entire cohort (2y-OS, 56% vs 96%; HR, 3.24; P = .0005) and in MRD-positive patients (2y-OS, 34% vs 100%; HR, 3.78; P = .003), but there was no significant effect of either conditioning regimen or donor source on outcome. Registered at ISRCTN (http://www.isrctn.com/ISRCTN55675535).

Prophylactic donor lymphocyte infusion after allogeneic stem cell transplantation in acute leukaemia - a matched pair analysis by the Acute Leukaemia Working Party of EBMT.

Strategies for relapse prevention after allogeneic transplantation in acute leukaemia are warranted. A registry-based matched-pair analysis evaluated the efficacy of prophylactic donor lymphocyte infusion (proDLI). Adults receiving proDLI in complete remission (CR) and controls were pair-matched for age, diagnosis, cytogenetics, stage, donor, gender, conditioning and T-cell depletion. Eighty-nine pairs were identified (median follow-up: 6.9 years). Within the entire cohort, no difference was observed. However, among patients with high-risk acute myeloid leukaemia (AML) (unfavourable cytogenetics and/or transplanted beyond first CR), proDLI recipients had improved overall survival (69.8% vs. 40.2% in controls, P = 0.027). ProDLI has moderate efficacy, but can contribute to improved outcome in high-risk AML.

Sociodemographic and psychological determinants of influenza vaccine intention among recipients of autologous and allogeneic haematopoietic stem cell transplant: a cross-sectional survey of UK transplant recipients using a modified health belief model.

OBJECTIVES: Studies exploring vaccination rates among haematopoietic stem cell transplant (HSCT) recipients have focused on physician factors that limit uptake. Understanding the patient factors that determine vaccination intention is crucial to delivering a successful vaccination programme. Using a modified health belief model (mHBM), we conducted a cross-sectional survey with the objective of exploring the sociodemographic and psychological factors that determined autologous and allogeneic HSCT recipients' intention to receive the seasonal inactivated influenza vaccine (SIIV) during the 2015-2016 influenza season. SETTING: The setting of our study was three tertiary level, UK National Health Service (NHS) autologous and allogeneic HSCT centres. PARTICIPANTS: Eligible patients were aged 16 years or over and recipients of autologous or allogeneic HSCT for any disease indication, with no absolute contraindication to receiving the SIIV during the next influenza season, and having not received the SIIV since transplant. 93 participants from 3 UK NHS HSCT centres completed an anonymous study-specific questionnaire. 78.5% were recipients of allogeneic and 21.5% autologous HSCT. RESULTS: 23.7% of participants expressed low intent to receive the SIIV. Patients aged over 65 (OR 0.02, 95% CI 0.01 to 0.57, p=0.02) and those who had not received the SIIV prior to HSCT (OR 0.04, 95% CI 0.02 to 0.56, p=0.02) were less likely to have high intent. A multivariate logistic regression model incorporating constructs of the mHBM was statistically significant (p<0.001) and explained 74.7% of variation in SIIV intention. More patients felt that a recommendation from their HSCT team than their general practitioner would prompt them to receive the SIIV, and this was most pronounced in those who had low intent. CONCLUSIONS: The mHBM may provide a useful structure for addressing low vaccine intent among HSCT recipients and further interventional studies are warranted. We would encourage HSCT and general practitioners to discuss SIIV intention as a routine part of care.

Bradycardia following retinoic acid differentiation syndrome in a patient with acute promyelocytic leukaemia.

The authors describe a 28-year-old woman with newly diagnosed acute promyelocytic leukaemia (APL), who developed junctional bradycardia after receiving the molecular-targeted therapy all-trans retinoic acid (ATRA) and the anthracycline-based chemotherapeutic agent idarubicin following sepsis and the APL differentiation syndrome. The patient was asymptomatic of the bradycardia. Electrolytes and cardiac imaging were unremarkable. No other cases have been reported in this context and the mechanisms of the sinus node dysfunction are unclear. The patient achieved normal sinus rhythm after ATRA was withheld. The patient recovered and went on to achieve complete remission after re-starting ATRA and idarubicin.