Myelodysplastic Neoplasms (MDS)

MyeloDysplaStic neoplasms (MDS, the WHO classification 2022 uses the term "myelodysplastic neoplasms" [1], however continues the abbreviation "MDS") are clonal diseases of the hematopoietic stem cell characterized by dysplasia of blood and bone marrow cells associated with hematopoietic insufficiency and increased risk of developing acute myeloid leukemia (AML). Therapy-associated MDS (approx. 10 %) can occur after previous chemotherapy and/or radiotherapy. In approx. 90 % of cases, a noxious agent remains unknown. The prominent finding is usually anemia, often also bi- or pancytopenia. The bone marrow is often normo- or hypercellular, in about 10% of cases hypocellular. Dysplasia signs of one or more cell rows are diagnostically indicative. It is mandatory that at least 10 % of the cells of one cell row must show clear signs of dysplasia.

MDS are among the most common malignant hematologic disorders, with an incidence of approximately 4-5/100,000 inhabitants per year [2]. At ages older than 70 years, the incidence increases to >30/100,000. The median age of onset is approximately 75 years, and women are affected slightly less frequently than men.

The pathogenesis of MDS represents a complex process in which a gradual accumulation of genomic damage (DNA mutations) and epigenetic changes in hematopoietic stem cells is assumed to be causative. It is assumed that this leads to a selection of malignant stem cells, which increasingly colonize the bone marrow with their progenitor cells and displace the healthy hematopoiesis. In the last decade, the availability of high-throughput molecular methods has identified numerous new molecular lesions that are recurrent but not exclusive in MDS. In approximately 50% of MDS chromosomal alterations are seen. Other mutations are mainly point mutations, which were detected in genes of the splicing apparatus (e.g., SF3B1, SRSF2, ZRSR2, U2AF1, PRPF8), of regulators of epigenetic modifications (e.g. DNMT3A, TET2, ASXL1, IDH1/2, EZH2, WT1), of transcription factors (e.g. RUNX1, TP53, ETV6, GATA2, BCOR, BCORL1, CUX1), of the cohesin complex (STAG2, RAD21, SMC3), of the RAS pathway (PTPN11, NF1, NRAS, KRAS, CBL), of cytokine receptors and tyrosine kinases (CSF3R, FLT3, KIT, MPL) and others [3]. In approximately 95% of all MDS patients, at least one of the recurrent mutations and/or karyotype alterations is detectable.

In addition to alterations in hematopoietic stem cells, disorders in the bone marrow microenvironment (niche) became apparent in recent years. Initial experimental work has demonstrated that genetic damage in the bone marrow stroma alone may be sufficient to generate an MDS phenotype. Furthermore, xenotransplantation experiments of primary MDS cells in immuno-deficient mice demonstrated that hematopoietic cells from MDS patients need bone marrow stroma support for disease maintenance. Here, diseased MDS hematopoiesis apparently exerts an instructive effect on the bone marrow niche, which in turn creates favorable growth conditions for MDS cells [4].

Several individual factors, alone or in combination, may favor the development of MDS. Etiologically, primary forms of MDS and therapy-associated (secondary) forms are distinguished.

In secondary MDS, the changes in hematopoiesis occur after previous radiation and/or chemotherapy. In particular, treatment with alkylating agents in combination with radiation therapy (e.g., for lymphoma, mammary Ca) is associated with the risk of occurrence of MDS as a secondary neoplasia. The latency period for the appearance of MDS in these cases is on average 2-6 years.

A special form of the disease is MDS following long-term exposure to substances containing benzene or other organic solvents. Typically, affected persons are former service station employees, painters and varnishers, and airport employees (refueling of aircraft with kerosene). The prerequisite for recognition as an occupational disease in these cases is a long-lasting exposure (usually 10-20 years) to the chemicals mentioned.

In connection with the frequent occurrence of leukemia after radiation exposure (atomic bombing in Japan in 1945, reactor accident in Chernobyl in 1986), increased numbers of myeloid neoplasms, which rapidly turned into acute leukemia, were observed. These experiences suggest that high radiation exposure causes changes in hematopoiesis that may lead to the development of MDS.

Diseases that occur without evidence of the factors presented are classified as a primary MDS. In recent years, germline mutations have been identified that are associated with a familial risk of MDS or AML. As the age of onset can be around 60-70 years even with germline mutations (e.g., DDX41 mutation), exploration of family history is important here.

Due to the lack of clear associations between certain pathogenic noxae and the development of MDS, no effective preventive measures are available. Compliance with occupational health and safety regulations when handling chemicals and radioactive radiation are part of primary prophylaxis.

Potential early forms of MDS are classified depending on the presence of cytopenias and cytogenetic or molecular alterations (Table 1) [1, 5]. These subgroups have in common that they do not (yet) fulfill the criteria of MDS.

ICUS (idiopathic cytopenia of undetermined significance) is defined by cytopenia and by the absence of molecular or cytogenetic aberrations.

In IDUS (idiopathic dysplasia of undetermined significance), only dysplastic changes in the bone marrow can be detected.

In CHIP (clonal hematopoiesis of indeterminate potential), molecular mutations can be detected, and DNMT3A, TET2, ASXL1 and splicing factors are mainly affected [6, 7]. However, cytopenia is not present. Per se, these are benign changes found mainly in the elderly. Clinically, the risk of developing manifest MDS or other malignant hematologic disease is significantly increased. Furthermore, mortality is increased (compared to reference populations) due to non-hematologic causes such as cardio-vascular complications.

In CCUS (clonal cytopenia of undetermined significance), cytopenia is present in addition to molecular aberrations. CCUS has been defined as a new entity in the WHO and ICC classifications [1, 5]. Depending on the individual disease course, control examinations are recommended approximately every 3-6 months, especially in the presence of molecular mutations.

After exclusion of numerous differential diagnoses (see chapter 5.6), MDS diagnostics include the preparation of a blood count, differential blood count and a bone marrow examination (see chapter 5.2).

The required diagnostics are shown in Table 2. The focus is on the cytomorphology of the blood and bone marrow including iron staining. (Examples in eLCH - eLearning Curriculum Hematology for bone marrow cytology using virtual microscopy; https://ehaematology.com/). Morphologically, it is important to determine the peripheral and medullary blast counts as exact as possible. According to the the IPSS-R [8], an exact determination of the medullary blast percentage is of high prognostic relevance (0-2% vs. 3-4% vs. 5-9% vs. 10-19%). It is also obligatory to determine whether the signs of dysplasia affect only one cell line or whether 2 or 3 cell lines are affected. These parameters allow classification into one of the WHO types [1]. In addition to cytology, bone marrow histology is also obligatory because it enables to assess changes of the bone marrow architecture, as well as bone marrow cellularity and fibrosis.

Immunophenotyping is becoming increasingly important as a tool to estimate the blast percentage and to show signs of dysplasia. However, the validity of this method in routine should not be overestimated. In clinical practice, immunophenotyping is used in particular to exclude differential diagnoses.

The types traditionally assigned to MDS are separated into two major groups in the current WHO classification (Table 3). In addition to pure MDS, a group of mixed myelodysplastic-myeloproliferative neoplasms is defined. The blast percentage discriminating from acute leukemia is 20% in blood and bone marrow. However, the prognostic score for MDS (IPSS-R; which was mandatory until 2022), still includes patients with up to 30% blasts [8]. Chromosomal analysis and screening for somatic mutations is essential for a clear diagnosis and treatment decision in MDS, as this is the only way to determine the patient's prognosis as exact as possible.

The 2022 WHO classification proposals are based on a new principle, namely the classification of MDS into morphologically defined and genetically defined types [1]. In addition, three new MDS types were defined as distinct entities for the first time. Other types are adopted unchanged from the old WHO classifications. Peripheral cell counts now have less weight in the classification.

In the group of morphologically defined MDS, two entirely new types have been defined in which no association with genetic characteristics is known so far. Both entities can only be diagnosed by bone marrow histology. In MDS with fibrosis, marrow fibrosis grade 2-3 and blast proliferation are present. Hypoplastic MDS is characterized by bone marrow cellularity of (age-adjusted) 25% and no elevated blast count. Estimation of bone marrow cellularity is more reliably with histology than with smear cytology; therefore, in light of these two new entities, histologic evaluation of the bone marrow is now mandatory at diagnosis. The group of MDS without blast proliferation, divided into single-lineage dysplasias and multilineage dysplasias (MDS SLD vs. MDS MLD), has been adopted unchanged from the older WHO classifications. MDS with blast multiplication also remained the same, except that EB1 and EB2 now became IB1 and IB2, as the term "Excess" was replaced by "Increased".

The definition of MDS del(5q) has been refined, as the presence of a bi-allelic TP53 mutation now leads to classification into a prognostically less favorable subgroup. However, a mono-allelic TP53 mutation is compatible with this subgroup (MDS del(5q)). In addition, a hierarchy of genetic alterations was agreed upon, as evidence of a del(5q) was prioritized over evidence of an SF3B1 mutation, and thus patients with MDS del(5q) and evidence of an SF3B1 mutation would not result in classification into the group of MDS with SF3B1 mutation. This was done in light of registry data that had shown that neither the clinical nor therapeutic course of patients with MDS del(5q) with or without evidence of ring sideroblasts was distinct. In contrast, patients with SF3B1 mutation and 5q deletion showed a significantly less favorable prognosis than patients with SF3B1 mutation and intact chromosome 5.

A similar classification has been published by an International Consensus Group (ICC), which differs only slightly from the WHO proposals with regard to MDS. However, the group of MDS with elevated blasts type 2 (bone marrow blasts >9%) is referred to as the MDS/AML category. The MDS with elevated blasts type 2 have a less favorable course compared with the MDS with elevated blasts type 1 (bone marrow blasts <10%) [5].

The genomic landscape MDS is heterogeneous and complex with cytogenetic and molecular components of diagnostic and prognostic relevance. Chromosomal abnormalities may occur in isolation or accompanied by other karyotype changes. The same applies analogously to gene mutations. Chromosomal and molecular abnormalities often occur in combination. In the IPSS-M cohort (n=2,957), 3,186 cytogenetic alterations were detected in 41% of patients and 9,254 oncogenic mutations in 121 genes were detected in 90% of patients. 94% of patients had at least 1 abnormality (median 4). 53% had exclusively molecular mutations, 4% had exclusively karyotype alterations, and 37% had both.

The genes most frequently mutated in MDS [9] include TET2 (30%), ASXL1 (27%), SF3B1 (26%), DNMT3A (17%), SRSF2 (16%), RUNX1 (13%), TP53 (12%), STAG2 and U2AF1 (9% each), EZH2, ZRSR2 and BCOR (7-8% each), CBL (6%), IDH2 (5%), NRAS, CUX1, SETBP1, PHF6 and NF1 (4% each), DDX41, KRAS, MLL/KMT2A, IDH1 and JAK2 (2-3% each).

In addition to age, gender, and comorbidities, disease biology parameters can be used to estimate prognosis. The most important prognostic parameters are the medullary blast percentage, cytogenetic and molecular genetic findings, followed by transfusion requirements, blood cell counts and serum LDH [10, 11].

MDS are dynamic diseases. All relevant parameters such as blood count, bone marrow morphology, cytogenetics and molecular genetics may change in the natural course of the disease as well as during therapy. This can lead to relevant consequences for the therapy strategy e.g. concerning the decision for an allogeneic stem cell transplantation or therapy renunciation or discontinuation. Thus, in longitudinal studies, karyotype evolution can be expected in up to 30% of patients and molecular evolution in up to 70%, which can massively influence the risk stratification and per se represent an unfavorable prognostic criterion. It is obvious that these data must find their way into a lege artis clinical management with the performance of sequential analyses. This is of great importance, if in the individual case it is to be expected that a risk stratification may change and that therapeutic consequences may result. Relevant analyses in this regard include bone marrow cytology, cytogenetics, and molecular genetics and, in the presence of myelofibrosis, histology. It has been shown that the strategy of initiating these diagnostics only in the case of significant blood count changes leads to a progression often being detected too late to be able to react therapeutically in a target-oriented manner. On the other hand, the value of sequential genetic analyses for therapy monitoring has been demonstrated in clinical trials. Therefore, a prospectively designed diagnostic strategy is recommended if this would have clinical consequences (Table 6).

Algorithms for the therapy of patients with myelodysplastic neoplasms are shown in Figure 1 and Figure 3. Whenever possible, patients should be treated in the context of clinical trials.

In all patients with high-risk MDS, the option of allogeneic stem cell transplantation should be considered already at diagnosis. Patients who are not eligible for this procedure may receive treatment with azacitidine or decitabine. In case of progression and failure to respond after 4-6 cycles, patients should be enrolled in ongoing clinical trials, if possible (Figure 3).

Further information is available from the German MDS Study Group, the Düsseldorf MDS Registry, and the European MDS Study Office (EMSCO).