Identification of chronic myeloid leukemia patients treated with imatinib who are potentially eligible for treatment discontinuation by assessing real-life molecular responses on the international scale in a EUTOS-certified lab.

A retrospective study was performed to describe molecular responses (MR) on the international scale (IS) in patients with chronic myeloid leukemia (CML) treated with imatinib in routine clinical practice in Belgium and to identify patients potentially eligible for treatment discontinuation. The analysis included 116 patients with CML in chronic phase at treatment centers sending blood samples for molecular follow-up to a single EUTOS-certified laboratory. IS MR from the last patient visit between October 2014 and April 2015 were retrospectively collected. Most patients (93.1%) had an IS MR corresponding to an optimal response per European LeukemiaNet 2013 guidelines; 53.4% (62/116) of patients were in deep molecular responses ≥MR4.5 at their last visit (mean treatment duration: 91.0 months) among whom 36.2% (42/116) had been receiving imatinib for >5.8 years and 26.7% (31/116) for >8 years (margins of error: 8.74% and 8.05%, respectively). These patients would likely have the highest chance of staying in treatment-free remission (TFR) upon discontinuation, based on published TFR trial data. Although our study only provides a snapshot in time of a patient's last MR reported, without precise information regarding MR duration, the study settings could nevertheless support the feasibility of attempting TFR outside clinical trials in the future.

Spectral domain optical coherence tomography findings in early deferoxamine maculopathy: report of two cases.

PURPOSE: To describe spectral domain optical coherence tomography features in two cases of early deferoxamine induced retinal toxicity. METHODS: Two patients complained of sudden bilateral visual loss and dyschromatopsia. Both suffered from acute myelocytic leukemia with severe aplastic anemia and were treated with intravenous deferoxamine for 1 month. First ophthalmologic exploration and follow-up included fundoscopic examination, fluorescence angiography, fundus autofluorescence, and spectral domain optical coherence tomography. RESULTS: Initially, both patients presented with a decreased visual acuity, inferior to 20/100. Fundus examination revealed a loss of transparency of the outer retina in the two cases. Autofluorescence pictures displayed hypoautofluorescence in the macular area, whereas fluorescein angiography unveiled an annular hyperfluorescence staining in the macular zone. Spectral domain optical coherence tomography showed a serous detachment of the neuroepithelium associated with photoreceptor outer segment elongation. Deferoxamine toxicity was immediately suspected and therapy promptly interrupted. One week later, both patients recovered visual acuity of 20/20 but retinal pigment epithelium (RPE) mottling was noticed in the macular areas. Spectral domain optical coherence tomography monitoring showed a progressive resolution of serous retinal detachment. Elongation of the photoreceptor outer segment disappeared but the RPE remained thickened, interrupted, and fragmented at different macular loci. CONCLUSION: Serous detachment of the neuroepithelium associated with photoreceptor outer segment elongation in the early stage of deferoxamine maculopathy is described for the first time. Early drug discontinuation allowed a fast resolution of the serous detachment but the typical RPE pigment mottling observed at the resolution phase was noticed 1 week later.

The cholinergic anti-inflammatory pathway delays TLR-induced skin allograft rejection in mice: cholinergic pathway modulates alloreactivity.

Activation of innate immunity through Toll-like receptors (TLR) can abrogate transplantation tolerance by revealing hidden T cell alloreactivity. Separately, the cholinergic anti-inflammatory pathway has the capacity to dampen macrophage activation and cytokine release during endotoxemia and ischemia reperfusion injury. However, the relevance of the α7 nicotinic acetylcholine receptor (α7nAChR)-dependent anti-inflammatory pathway in the process of allograft rejection or maintenance of tolerance remains unknown. The aim of our study is to investigate whether the cholinergic pathway could impact T cell alloreactivity and transplant outcome in mice. For this purpose, we performed minor-mismatched skin allografts using donor/recipient combinations genetically deficient for the α7nAChR. Minor-mismatched skin grafts were not rejected unless the mice were housed in an environment with endogenous pathogen exposure or the graft was treated with direct application of imiquimod (a TLR7 ligand). The α7nAChR-deficient recipient mice showed accelerated rejection compared to wild type recipient mice under these conditions of TLR activation. The accelerated rejection was associated with enhanced IL-17 and IFN-γ production by alloreactive T cells. An α7nAChR-deficiency in the donor tissue facilitated allograft rejection but not in recipient mice. In addition, adoptive T cell transfer experiments in skin-grafted lymphopenic animals revealed a direct regulatory role for the α7nAChR on T cells. Taken together, our data demonstrate that the cholinergic pathway regulates alloreactivity and transplantation tolerance at multiple levels. One implication suggested by our work is that, in an organ transplant setting, deliberate α7nAChR stimulation of brain dead donors might be a valuable approach for preventing donor tissue inflammation prior to transplant.

Critical role of regulatory T cells in Th17-mediated minor antigen-disparate rejection.

Th17-mediated immune responses have been recently identified as novel pathogenic mechanisms in a variety of conditions; however, their importance in allograft rejection processes is still debated. In this paper, we searched for MHC or minor Ag disparate models of skin graft rejection in which Th17 immune responses might be involved. We found that T cell-derived IL-17 is critical for spontaneous rejection of minor but not major Ag-mismatched skin grafts. IL-17 neutralization was associated with a lack of neutrophil infiltration and neutrophil depletion delayed rejection, suggesting neutrophils as an effector mechanism downstream of Th17 cells. Regulatory T cells (Tregs) appeared to be involved in Th17 reactivity. We found that in vivo Treg depletion prevented IL-17 production by recipient T cells. An adoptive cotransfer of Tregs with naive monospecific antidonor T cells in lymphopenic hosts biased the immune response toward Th17. Finally, we observed that IL-6 was central for balancing Tregs and Th17 cells as demonstrated by the prevention of Th17 differentiation, the enhanced Treg/Th17 ratio, and a net impact of rejection blockade in the absence of IL-6. In conclusion, the ability of Tregs to promote the Th17/neutrophil-mediated pathway of rejection that we have described should be considered as a potential drawback of Treg-based cell therapy.

Donor T-cell development in host thymus after heterotopic limb transplantation in mice.

We developed a mouse model of heterotopic limb transplantation in which we took advantage of Thy1.1 and Thy1.2 congenic strains to track and characterize donor T cells, to determine the role of recipient's thymus in mixed T-cell chimerism induction as well as transplant immunocompetence. The vascularized Thy1.1 limb graft composed of femur, muscle, and skin (VBT) survived long-term in more than 87.5% of Thy1.2 recipients. Percentages of donor-type Thy1.1 T cells increased from day 30 to 90 in thymus and spleen of recipients. Most peripheral donor T cells displayed a naïve phenotype and a few others were regulatory T cells. Thymectomy prevented peripheral T-cell chimerism. Congenic VBT in immunodeficient RAG mice restored their ability to reject skin allografts. These observations suggest that donor T cells differentiated in host thymus might contribute to maintenance of mixed chimerism after transplantation of tissue composite grafts that include vascularized bone.