Surveillance of Myelodysplastic Syndrome via Migration Analyses of Blood Neutrophils: A Potential Prognostic Tool

Schuster, Marc; Moeller, Mischa; Bornemann, Lea; Bessen, Clara; Sobczak, Charlyn; Schmitz, Saskia; Witjes, Laura; Kruithoff, Katja; Kohn, Christina; Just, Olga; Kündgen, Andrea; Pundt, Noreen; Pelzer, Benedikt W.; Ampè, Christophe; Troys, Marleen Van; Nusch, Arnd; Haas, Rainer; Germing, Ulrich; Martens, Lennart; Jöckel, Karl‐Heinz; Gunzer, Matthias

doi:10.4049/jimmunol.1801071

Cited by 23 publications

(61 citation statements)

References 52 publications

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“…In fact, automated tracking analysis revealed that already the baseline percentage of moving cells and their speed were reduced in aCML neutrophils (54.9 %, 6.33 µm/min) compared to control values (71.90 ± 4.01 %, 8.457 ± 0.47 µm/min) ( Figure 1E Figure 1E). Taken together, neutrophils from this aCML case displayed impaired migration comparable to the previously published nding of neutrophils from MDS patients (13).…”

Section: Acml Neutrophil Migratory Impairmentsupporting

confidence: 86%

“…In this regard, we recently demonstrated that neutrophil migration strongly correlates with the revised international prognosis scoring system (IPSS-R) in myelodysplastic syndrome (13), representing a neoplasia affecting neutrophil functions such as degranulation and phagocytosis (14). Here, neutrophils from severe MDS cases, with a high risk of blast transformation, displayed signi cantly lower migration speed than lower-risk MDS cases or neutrophils from healthy donors.…”

Section: Introductionmentioning

confidence: 89%

“…All blood samples were obtained in EDTAsupplemented tubes and transported for 30 minutes up to 1 hour in a VACUETTE® transport container (VTC) (Greiner Bio-One, Kremsmünster, Austria) according to the UN 3373 regulation. Figure 2A) and as previously detailed (13). The neutrophil migration assay was performed as previously described (13).…”

Section: Blood Samplesmentioning

confidence: 99%

“…Figure 2A) and as previously detailed (13). The neutrophil migration assay was performed as previously described (13). Brie y, puri ed neutrophils were seeded in a 96 Well µ-Plate (Cat.…”

Section: Blood Samplesmentioning

confidence: 99%

“…Here, neutrophils from severe MDS cases, with a high risk of blast transformation, displayed signi cantly lower migration speed than lower-risk MDS cases or neutrophils from healthy donors. Furthermore, the recovery of normal migration patterns during therapy correlated with a successful response to the treatment, pointing at the analysis of migration as a potential monitoring tool for therapy (13).…”

Section: Introductionmentioning

confidence: 96%

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Defective migration and dysmorphology of neutrophil granulocytes in atypical chronic myeloid leukemia treated with ruxolitinib

Bornemann

Schuster

Schmitz

et al. 2020

Preprint

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Abstract Background The identification of pathologically altered neutrophil granulocyte migration patterns bears strong potential for surveillance and prognostic scoring of diseases. We recently identified a strong correlation between impaired neutrophil motility and the disease stage of myelodysplastic syndrome (MDS). Here, we apply this assay to study quantitively increased neutrophils of a patient suffering from a rare leukemia subtype, atypical chronic myeloid leukemia (aCML).Methods A 69-year-old male was analyzed in this study. Besides routine analyses, we purified the patient’s neutrophils from peripheral whole blood and studied their migration behavior using time-lapse video microscopy in a standardized assay. These live cell migration analyses also allowed for the quantification of cell morphology. Furthermore, the cells were stained for the markers CD15, CD16, fMLPR, CXCR1 and CXCR2. Results Despite cytoreductive therapy with hydroxyurea, the patient’s WBC and ANC were poorly controlled and severe dysgranulopoiesis with hypogranularity was observed. Neutrophils displayed strongly impaired migration when compared to healthy controls and migrating cells exhibited a more flattened-out morphology than control neutrophils. Because of a detected CSF3R (p.T618I) mutation and constitutional symptoms treatment with ruxolitinib was initiated. Within one week of ruxolitinib treatment, the cell shape normalized and remained indistinguishable from healthy control neutrophils. However, neutrophil migration did not improve over the course of ruxolitinib therapy but was strikingly altered shortly before a sinusitis with fever and bleeding from a gastric ulcer. Molecular work-up revealed that under ruxolitinib treatment, the CSF3R clone was depleted, yet the expansion of a NRAS mutated subclone was promoted. Conclusion These results demonstrate the usefulness of neutrophil migration analyses to uncover corresponding alterations of neutrophil migration in rare myeloid neoplasms. Furthermore, in addition to monitoring migration the determination of morphological features of live neutrophils might represent a useful tool to monitor the effectiveness of therapeutic approaches.

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Section: Acml Neutrophil Migratory Impairmentsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 89%

Section: Blood Samplesmentioning

confidence: 99%

“…Figure 2A) and as previously detailed (13). The neutrophil migration assay was performed as previously described (13). Brie y, puri ed neutrophils were seeded in a 96 Well µ-Plate (Cat.…”

Section: Blood Samplesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

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Defective migration and dysmorphology of neutrophil granulocytes in atypical chronic myeloid leukemia treated with ruxolitinib

Bornemann

Schuster

Schmitz

et al. 2020

Preprint

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Impact of treatment intensity on infectious complications in patients with acute myeloid leukemia

Tober

Schnetzke

Fleischmann

et al. 2022

J Cancer Res Clin Oncol

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Background Infectious complications reflect a major challenge in the treatment of patients with acute myeloid leukemia (AML). Both induction chemotherapy and epigenetic treatment with hypomethylating agents (HMA) are associated with severe infections, while neutropenia represents a common risk factor. Here, 220 consecutive and newly diagnosed AML patients were analyzed with respect to infectious complications dependent on treatment intensity and antifungal prophylaxis applied to these patients. Patients and methods We retrospectively analyzed 220 patients with newly diagnosed AML at a tertiary care hospital between August 2016 and December 2020. The median age of AML patients undergoing induction chemotherapy (n = 102) was 61 years (25–76 years). Patients receiving palliative AML treatment (n = 118) had a median age of 75 years (53–91 years). We assessed the occurrence of infectious complication including the classification of pulmonary invasive fungal disease (IFD) according to the EORTC/MSG criteria at diagnosis and until day 100 after initiation of AML treatment. Furthermore, admission to intensive care unit (ICU) and subsequent outcome was analyzed for both groups of AML patients, respectively. Results AML patients subsequently allocated to palliative AML treatment have a significantly higher risk of pneumonia at diagnosis compared to patients undergoing induction chemotherapy (37.3% vs. 13.7%, P < 0.001) including a higher probability of atypical pneumonia (22.0% vs. 10.8%, P = 0.026). Furthermore, urinary tract infections are more frequent in the palliative subgroup at the time of AML diagnosis (5.1% vs. 0%, P = 0.021). Surprisingly, the incidence of pulmonary IFD is significantly lower after initiation of palliative AML treatment compared to the occurrence after induction chemotherapy (8.4% vs. 33.3%, P < 0.001) despite only few patients of the palliative treatment group received Aspergillus spp.-directed antifungal prophylaxis. The overall risk for infectious complications at AML diagnosis is significantly higher for palliative AML patients at diagnosis while patients undergoing induction chemotherapy have a significantly higher risk of infections after initiation of AML treatment. In addition, there is a strong correlation between the occurrence of pneumonia including atypical pneumonia and pulmonary IFD and the ECOG performance status at diagnosis in the palliative AML patient group. Analysis of intensive care unit (ICU) treatment (e.g. in case of sepsis or pneumonia) for both subgroups reveals a positive outcome in 10 of 15 patients (66.7%) with palliative AML treatment and in 15 of 18 patients (83.3%) receiving induction chemotherapy. Importantly, the presence of infections and the ECOG performance status at diagnosis significantly correlate with the overall survival (OS) of palliative AML patients (315 days w/o infection vs. 69 days with infection, P 0.0049 and 353 days for ECOG < 1 vs. 50 days for ECOG > 2, P < 0.001, respectively) in this intent-to-treat analysis. Conclusion The risk and the pattern of infectious complications at diagnosis and after initiation of AML therapy depends on age, ECOG performance status and subsequent treatment intensity. A comprehensive diagnostic work-up for identification of pulmonary IFD is indispensable for effective treatment of pneumonia in AML patients. The presence of infectious complications at diagnosis contributes to an inferior outcome in elderly AML patients.

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Automated characterisation of neutrophil activation phenotypes in ex vivo human Candida blood infections

Belyaev

Marolda

Praetorius

et al. 2022

Computational and Structural Biotechnology Journal

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Surveillance of Myelodysplastic Syndrome via Migration Analyses of Blood Neutrophils: A Potential Prognostic Tool

Cited by 23 publications

References 52 publications

Defective migration and dysmorphology of neutrophil granulocytes in atypical chronic myeloid leukemia treated with ruxolitinib

Defective migration and dysmorphology of neutrophil granulocytes in atypical chronic myeloid leukemia treated with ruxolitinib

Impact of treatment intensity on infectious complications in patients with acute myeloid leukemia

Automated characterisation of neutrophil activation phenotypes in ex vivo human Candida blood infections

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