Summary
This article reviews the use of aberrant antigen expression detected by flow cytometry in the diagnosis and clinical handling of acute myeloid leukaemia (AML) and the myelodysplastic ...syndromes (MDS). Such aberrancies offer a valuable tool for the proper classification of these myeloid malignancies according the World Health Organization 2008 classification. Aberrant antigen expression by flow cytometry is also important for prognostification. This review supports the view, that minimal residual disease detection methods that make use of such aberrancies should be part of the routine management of AML patients to guide therapy, but also suggests the introduction of flow cytometry in MDS for diagnosis and treatment decisions in the near future.
We report on a series of sequential events leading to long-term survival and cure of pediatric X-linked chronic granulomatous disease (X-CGD) patients after gamma-retroviral gene therapy (GT) and ...rescue HSCT. Due to therapyrefractory life-threatening infections requiring hematopoietic stem cell transplantation (HSCT) but absence of HLAidentical donors, we treated 2 boys with X-CGD by GT. Following GT both children completely resolved invasive Aspergillus nidulans infections. However, one child developed dual insertional activation of ecotropic viral integration site 1 (EVI1) and signal transducer and activator of transcription 3 (STAT3) genes, leading to myelodysplastic syndrome (MDS) with monosomy 7. Despite resistance to mismatched allo-HSCT with standard myeloablative conditioning, secondary intensified rescue allo-HSCT resulted in 100 % donor chimerism and disappearance of MDS. The other child did not develop MDS despite expansion of a clone with a single insertion in the myelodysplasia syndrome 1 (MDS1) gene and was cured by early standard allo-HSCT. The slowly developing dominance of clones harboring integrations in MDS1-EVI1 may guide clinical intervention strategies, i.e. early rescue allo-HSCT, prior to malignant transformation. GT was essential for both children to survive and to clear therapy-refractory infections, and future GT with safer lentiviral self-inactivated (SIN) vectors may offer a therapeutic alternative for X-CGD patients suffering from life-threatening infections and lacking HLA-identical HSC donors.
Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic stem cell disorders characterized by ineffective hematopoiesis with abnormal blood cell development (dysplasia) leading to ...cytopenias and an increased risk for progression to acute myeloid leukemia (AML). Patients with MDS can generally be classified as lower- (LR-MDS) or higher-risk (HR-MDS). As treatment goals for patients with LR-MDS and those with HR-MDS differ significantly, appropriate diagnosis, classification, and follow-up are critical for correct disease management. In this review, we focus on the diagnosis, prognosis, and treatment options, as well as the prediction of the disease course and monitoring of treatment response in patients with LR-MDS. We discuss how next-generation sequencing, increasing knowledge on mechanisms of MDS pathogenesis, and novel therapies may change the current treatment landscape in LR-MDS and why structured assessments of responses, toxicities, and patient-reported outcomes should be incorporated into routine clinical practice.
Highlights • The age-standardized incidence rate (ASR) per 100,000 was 5.4 for MDS and 0.4 for CMML. • The ASR of MDS was almost 2-fold higher than in the Netherlands Cancer Registry (NCR). • Almost ...half of all cases were diagnosed without a bone marrow examination (BM). • The ASR in the MDS cohort with BM examinations was comparable with the NCR. • The majority of patients, either with or without BM examinations, received no therapy.
Dendritic cells (DC) are increasingly applied in the immunotherapy of cancer. As the development of a standardized DC vaccine product is often hampered by the limited availability of DC precursors ...and inter- and intra-donor variability, and the preparation of individual vaccines is labor-intensive, it would be preferable to use DC from a readily available and unlimited source, such as cell lines can provide. It has been described that leukemia-derived cell lines are able to differentiate into functional DC, creating possibilities for the development of highly reproducible DC vaccines and providing in vitro model systems for in-depth studies about DC physiology. This review discusses the different human DC cell line differentiation models described so far. Based on the available data, characteristics that determine the ability of leukemia cells to differentiate along the different precursor stages into functional DC will be formulated. In addition, evidence will be provided that the human CD34+ acute myeloid leukemia cell line MUTZ-3 provides DC that exhibit the functional properties that are crucial for the in vivo generation of CTL-mediated immunity and thus, currently, represents the most valuable, sustainable model system for myeloid DC differentiation and clinical DC vaccination studies.
In myelodysplastic syndromes (MDSs), the evolution of risk for disease progression or death has not been systematically investigated despite being crucial for correct interpretation of prognostic ...risk scores. In a multicenter retrospective study, we described changes in risk over time, the consequences for basal prognostic scores, and their potential clinical implications. Major MDS prognostic risk scoring systems and their constituent individual predictors were analyzed in 7212 primary untreated MDS patients from the International Working Group for Prognosis in MDS database. Changes in risk of mortality and of leukemic transformation over time from diagnosis were described. Hazards regarding mortality and acute myeloid leukemia transformation diminished over time from diagnosis in higher-risk MDS patients, whereas they remained stable in lower-risk patients. After approximately 3.5 years, hazards in the separate risk groups became similar and were essentially equivalent after 5 years. This fact led to loss of prognostic power of different scoring systems considered, which was more pronounced for survival. Inclusion of age resulted in increased initial prognostic power for survival and less attenuation in hazards. If needed for practicability in clinical management, the differing development of risks suggested a reasonable division into lower- and higher-risk MDS based on the IPSS-R at a cutoff of 3.5 points. Our data regarding time-dependent performance of prognostic scores reflect the disparate change of risks in MDS subpopulations. Lower-risk patients at diagnosis remain lower risk whereas initially high-risk patients demonstrate decreasing risk over time. This change of risk should be considered in clinical decision making.
•Hazards regarding mortality and leukemic transformation in MDS diminish over time in higher-risk but remain stable in lower-risk patients.•This change of hazard indicates time-dependent attenuation of power of basal risk scores, which is relevant for clinical decision making.
The bone marrow of patients with low-risk myelodysplastic syndromes (MDS) is often an inflammatory environment and associated with an active cellular immune response. An active immune response ...generally contributes to antitumor responses and may prevent disease progression. However, chronic immune stimulation can also induce cell stress, DNA damage and contribute to the pathogenesis of MDS. The protective mechanisms against excessive immune activation are therefore an important aspect of the pathophysiology of MDS and characterizing them may help us to better understand the fine balance between protective and destabilizing inflammation in lower-risk disease. In this study we investigated the role of thrombomodulin (CD141/BDCA-3) expression, a molecule with anti-inflammatory properties, on monocytes in the bone marrow and peripheral blood of MDS patients in different risk groups. Patient-derived classical monocytes showed high expression levels of thrombomodulin, whereas monocytes from healthy donors hardly expressed any thrombomodulin. The presence of thrombomodulin on monocytes from MDS patients correlated with lower-risk disease groups and better overall and leukemia-free survival. Using multidimensional mass cytometry, in an
setting, we showed that thrombomodulin-positive monocytes could polarize naïve T cells toward cell clusters which are closer to T helper type 2 and T regulatory cell phenotypes and less likely to contribute to effective immune surveillance. In conclusion, the expression of thrombomodulin on classical monocytes is a favorable and early prognostic marker in patients with low-risk MDS and may represent a new mechanism in the protection against disproportionate immune activation.
Background: It was proposed that peripheral blood (PB) monocyte profiles evaluated by flow cytometry, called “monocyte assay,” could rapidly and efficiently distinguish chronic myelomonocytic ...leukemia (CMML) from other causes of monocytosis by highlighting an increase in the classical monocyte (cMo) fraction above 94%. However, the robustness of this assay requires a large multicenter validation and the assessment of its feasibility on bone marrow (BM) samples, as some centers may not have access to PB.
Methods: PB and/or BM samples from patients displaying monocytosis were assessed with the “monocyte assay” by 10 ELN iMDS Flow working group centers with harmonized protocols. The corresponding files were reanalyzed in a blind fashion and the cMo percentages obtained by both analyses were compared. Confirmed diagnoses were collected when available.
Results: The comparison between cMo percentages from 267 PB files showed a good global significant correlation (r = 0.88) with no bias. Confirmed diagnoses, available for 212 patients, achieved a 94% sensitivity and an 84% specificity. Hence, 95/101 CMML patients displayed cMo ≥94% while cMo <94% was observed in 83/99 patients with reactive monocytosis and in 10/12 patients with myeloproliferative neoplasms (MPN) with monocytosis. The established Receiver Operator Curve again provided a 94% cut‐off value of cMo. The 117 BM files reanalysis led to an 87% sensitivity and an 80% specificity, with excellent correlation between the 43 paired samples to PB.
Conclusions: This ELN multicenter study demonstrates the robustness of the monocyte assay with only limited variability of cMo percentages, validates the 94% cutoff value, confirms its high sensitivity and specificity in PB and finally, also confirms the possibility of its use in BM samples.
Rapid advances over the past decade have uncovered the heterogeneous genomic and immunologic landscape of myelodysplastic syndromes (MDS). This has led to notable improvements in the accuracy and ...timing of diagnosis and prognostication of MDS, as well as the identification of possible novel targets for therapeutic intervention. For the practicing clinician, however, this increase in genomic, epigenomic, and immunologic knowledge needs consideration in a "real-world" context to aid diagnostic specificity. Although the 2016 revision to the World Health Organization classification for MDS is comprehensive and timely, certain limitations still exist for day-to-day clinical practice. In this review, we describe an up-to-date diagnostic approach to patients with suspected lower-risk MDS, including hypoplastic MDS, and demonstrate the requirement for an "integrated" diagnostic approach. Moreover, in the era of rapid access to massive parallel sequencing platforms for mutational screening, we suggest which patients should undergo such analyses, when such screening should be performed, and how those data should be interpreted. This is particularly relevant given the recent findings describing age-related clonal hematopoiesis.
PDF
