The evaluation of bone marrow morphology by experienced hematopathologists is essential in the diagnosis of acute myeloid leukemia (AML); however, it suffers from a lack of standardization and ...inter-observer variability. Deep learning (DL) can process medical image data and provides data-driven class predictions. Here, we apply a multi-step DL approach to automatically segment cells from bone marrow images, distinguish between AML samples and healthy controls with an area under the receiver operating characteristic (AUROC) of 0.9699, and predict the mutation status of Nucleophosmin 1 (NPM1)-one of the most common mutations in AML-with an AUROC of 0.92 using only image data from bone marrow smears. Utilizing occlusion sensitivity maps, we observed so far unreported morphologic cell features such as a pattern of condensed chromatin and perinuclear lightening zones in myeloblasts of NPM1-mutated AML and prominent nucleoli in wild-type NPM1 AML enabling the DL model to provide accurate class predictions.
Graft-versus-host disease (GvHD) of the skin is a severe allo-immune reaction and complication following allogeneic stem cell transplantation. Over the past years, intensive pre-clinical research has ...led to an improved understanding of the pathophysiology of acute and to a lesser extend chronic GvHD. This has translated into the approval of several new agents for the treatment of both forms of GvHD. This review summarizes the most recent advances in underlying pathomechanisms, clinical trials and newly approved agents for GvHD, with a special focus on skin involvement.
JAK1/2 inhibitor ruxolitinib (RUX) is approved in patients with myelofibrosis but the impact of pretreatment with RUX on outcome after allogeneic hematopoietic stem cell transplantation (HSCT) ...remains to be determined. We evaluated the impact of RUX on outcome in 551 myelofibrosis patients who received HSCT without (n = 274) or with (n = 277) RUX pretreatment. The overall leukocyte engraftment on day 45 was 92% and significantly higher in RUX responsive patients than those who had no or lost response to RUX (94% vs. 85%, p = 0.05). The 1-year non-relapse mortality was 22% without significant difference between the arms. In a multivariate analysis (MVA) RUX pretreated patients with ongoing spleen response at transplant had a significantly lower risk of relapse (8.1% vs. 19.1%; p = 0.04) and better 2-year event-free survival (68.9% vs. 53.7%; p = 0.02) in comparison to patients without RUX pretreatment. For overall survival the only significant factors were age > 58 years (p = 0.03) and HLA mismatch donor (p = 0.001). RUX prior to HSCT did not negatively impact outcome after transplantation and patients with ongoing spleen response at time of transplantation had best outcome.
Myelodysplastic Syndromes and Metabolism Balaian, Ekaterina; Wobus, Manja; Bornhäuser, Martin ...
International journal of molecular sciences,
10/2021, Volume:
22, Issue:
20
Journal Article
Peer reviewed
Open access
Myelodysplastic syndromes (MDS) are acquired clonal stem cell disorders exhibiting ineffective hematopoiesis, dysplastic cell morphology in the bone marrow, and peripheral cytopenia at early stages; ...while advanced stages carry a high risk for transformation into acute myeloid leukemia (AML). Genetic alterations are integral to the pathogenesis of MDS. However, it remains unclear how these genetic changes in hematopoietic stem and progenitor cells (HSPCs) occur, and how they confer an expansion advantage to the clones carrying them. Recently, inflammatory processes and changes in cellular metabolism of HSPCs and the surrounding bone marrow microenvironment have been associated with an age-related dysfunction of HSPCs and the emergence of genetic aberrations related to clonal hematopoiesis of indeterminate potential (CHIP). The present review highlights the involvement of metabolic and inflammatory pathways in the regulation of HSPC and niche cell function in MDS in comparison to healthy state and discusses how such pathways may be amenable to therapeutic interventions.
Acute graft-versus-host disease (aGvHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Steroid-resistant aGvHD is associated with poor ...outcome, and no commonly accepted salvage therapy is available for its treatment. Here, we report 58 adult patients treated with mesenchymal stromal cells (MSCs) as salvage therapy for steroid-refractory aGvHD. Third-party MSCs expanded in platelet lysate-containing medium were transfused at a median dose of 0.99 × 10(6) cells per kg b.wt. A median of two MSC infusions were administered to each patient. Median time between the onset of aGvHD and the first infusion of MSCs was 12 days (range, 6-62 days). Most patients (79%) had grade IV aGvHD. Five patients showed complete response, five showed very good partial response, 17 showed partial response, and 31 showed no response. The estimated probability of survival after 1 year was 19%, and median survival was 69 days. Overall survival was not significantly different from that of a historical cohort of patients receiving alternative salvage therapy and no MSC infusions. In conclusion, MSC treatment on top of conventional immunosuppression was associated with an overall response rate of 47% but improved outcome in terms of survival remains to be shown.
Acute promyelocytic leukemia (APL) is considered a hematologic emergency due to high risk of bleeding and fatal hemorrhages being a major cause of death. Despite lower death rates reported from ...clinical trials, patient registry data suggest an early death rate of 20%, especially for elderly and frail patients. Therefore, reliable diagnosis is required as treatment with differentiation-inducing agents leads to cure in the majority of patients. However, diagnosis commonly relies on cytomorphology and genetic confirmation of the pathognomonic t(15;17). Yet, the latter is more time consuming and in some regions unavailable.
In recent years, deep learning (DL) has been evaluated for medical image recognition showing outstanding capabilities in analyzing large amounts of image data and provides reliable classification results. We developed a multi-stage DL platform that automatically reads images of bone marrow smears, accurately segments cells, and subsequently predicts APL using image data only. We retrospectively identified 51 APL patients from previous multicenter trials and compared them to 1048 non-APL acute myeloid leukemia (AML) patients and 236 healthy bone marrow donor samples, respectively.
Our DL platform segments bone marrow cells with a mean average precision and a mean average recall of both 0.97. Further, it achieves high accuracy in detecting APL by distinguishing between APL and non-APL AML as well as APL and healthy donors with an area under the receiver operating characteristic of 0.8575 and 0.9585, respectively, using visual image data only.
Our study underlines not only the feasibility of DL to detect distinct morphologies that accompany a cytogenetic aberration like t(15;17) in APL, but also shows the capability of DL to abstract information from a small medical data set, i. e. 51 APL patients, and infer correct predictions. This demonstrates the suitability of DL to assist in the diagnosis of rare cancer entities. As our DL platform predicts APL from bone marrow smear images alone, this may be used to diagnose APL in regions were molecular or cytogenetic subtyping is not routinely available and raise attention to suspected cases of APL for expert evaluation.
Retrospective, surrogate marker-based studies have found inconsistent associations between systemic iron overload (SIO) and adverse outcome in patients undergoing allogeneic stem cell transplantation ...(allo-SCT). As a consequence, the impact of SIO in this context remains under debate. The aim of this study was to test whether the objective pretransplant quantification of liver-iron content (LIC) by magnetic resonance imaging (MRI) could circumvent these limitations and conclusively define the prognostic relevance of SIO.
The correlation between pretransplant LIC and surrogate parameters as well as the impact of SIO on posttransplant outcome was assessed within an observational study of patients (n = 88) with either myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) undergoing allo-SCT.
Ferritin levels of 1,000 ng/mL or more provided only poor specificity (31.8%) for predicting elevated LIC (≥125 μmol/g) and even higher thresholds (≥2,500 ng/mL) lacked an association with nonrelapse mortality (NRM). In contrast, LIC 125 μmol/g or more was a significant risk factor for NRM in uni- and multivariate analysis (HR = 2.98; P = 0.016). Multivariate Cox-regression further showed that LIC 125 μmol/g or more was associated with a decreased overall survival (HR = 2.24, P = 0.038), whereas ferritin or transfusion burden were not.
SIO reflected by LIC is an independent negative prognostic factor for posttransplant outcome in patients with AML and MDS undergoing allo-SCT. Therefore, MRI-based LIC, and not interference-prone serum markers such as ferritin, should be preferred for pretransplant risk stratification and patient selection in future clinical trials.
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