Myelodysplastic Syndromes

Abstract

Background

Myelodysplastic syndromes (MDS) are malignant diseases arising from hematopoietic stem cells. Their overall incidence is 4 cases per 100 000 persons per year, and they are usually diagnosed when evaluating cytopenia. The median survival time is three years. Myelodysplastic syndromes take a variable course; one-quarter of patients go on to develop acute leukemia.

Methods

This review is based on publications retrieved by a selective search of the literature from 2013 to 2022, including relevant guidelines, in the PubMed database. The time period was chosen to reflect developments since the publication of the latest EHA guidelines in 2013.

Results

The gold standard of diagnosis is cytomorphology of the blood and bone marrow, supplemented by banding cytogenetics, histomorphology, and somatic mutation analyses. The new classification proposed by the WHO incorporates the molecular and cytogenetic findings. The Molecular International Prognostic Scoring System (IPSS-M), which takes somatic mutations into account, is now available as an aid to prognostication. Quality of life evaluation with standardized instruments is helpful in many ways. Low-risk patients are treated supportively with erythrocyte transfusions and iron chelation therapy. Erythropoietin-a can be given to patients whose erythropoietin level is less than 200ng/mL, lenalidomide to those with a 5q deletion, and luspatercept to those with an SF3B1 mutation. High-risk patients should be evaluated as early as possible for allogeneic hematopoietic stem cell transplantation with curative intent. 5-azacytidine improves outcomes in patients for whom stem cell transplantation is not suitable.

Conclusion

Once a precise diagnosis has been established, new prognostic instruments such as the IPSS-M enable risk-adapted treatment based on the biological aspects of the patient’s disease as well as his or her age and comorbidities.

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With an incidence of approximately 4 cases per 100 000 persons per year, myelodysplastic syndromes (MDS) are among the most common malignant diseases arising from stem cells. The incidence increases significantly with age. MDS are caused by genetic mutations that occur randomly and accumulate with age or are related to radiation or chemotherapy. The median age at onset is 70 to 75 years.

In the majority of cases, the etiology of the disease is unknown. However, it has been shown that patients diagnosed with clonal hematopoiesis of indeterminate potential (CHIP) based on somatic mutations, typically of the DNMT3A, TET2 and ASXL1 genes, are at a higher risk of developing MDS of about 0.5 to 1% per year. Prevalence increases with age and is estimated to be 10% at age 80 years and older. It is also known that germline mutations are more common in MDS than previously thought, in particular among younger adults (1– 3). The disease is caused by genetic alterations of hematopoietic stem cells. Progressive loss of differentiation and maturation results in functional impairment of blood cells, especially of platelets and granulocytes (4– 7). In many cases, this is associated with an increase in immature malignant precursor cells and an approximately 30% risk to develop acute myeloid leukemia (AML) within two years (8). Disease progression may also occur on the chromosomal level (9, 10). Besides cytomorphology, the diagnostic work-up should always include bone marrow histology, banding cytogenetics, and molecular testing for somatic mutations. Myelodysplastic syndromes take a variable course. While life expectancy is almost normal in some patients, there are also patients who develop acute leukemia within a few months and/or die from infections or hemorrhages. Thus, besides a precise diagnosis, the best possible estimation of the expected course of the disease is also relevant, as it is the basis for treatment planning. The Revised International Prognostic Scoring System (IPSS-R) or, if information about somatic mutations is available, its advanced version, the Molecular International Prognostic Scoring System (IPSS-M), is used for this purpose. Our review is based on publications retrieved by a selective search of the literature from 2013 to 2022 to reflect new developments since the last guidelines of the European Hematology Association (EHA), such as the updated WHO classification, the IPSS-molecular and new drug approvals. From the 8876 hits, original articles, pivotal clinical studies and consensus reviews were selected, also taking into account guidelines of the German Society of Hematology and Medical Oncology (DGHO) and NCCN guidelines. Clinical relevance for physicians practicing in Germany was the criterion for selection.

Diagnosis

Patients often present with symptoms of anemia or hemorrhage or incidental abnormal routine blood count results (box 1). An initial differential diagnostic evaluation to exclude iron, vitamin B12 and folate deficiencies, as well as hemolysis, among others, should be followed by special hematological tests. A normal routine blood count with differential makes bone marrow stem cell disease unlikely (11– 13). Bone marrow stem cell disease must be assumed especially in patients with bi- or pancytopenia. Besides deficiency anemias and hemolysis, key differential diagnoses include toxic bone marrow damage, immune-mediated cytopenia (immune thrombocytopenia/hemolysis), aplastic anemia, hereditary bone marrow diseases, paroxysmal nocturnal hemoglobinuria, but also acute myeloid leukemia and primary myelofibrosis. It is important to take past exposure to mutagenic agents, such as chemotherapy, radiotherapy and radioiodine therapy, into account, as these increase the risk of stem cell disease. Approximately 10% of patients have therapy-related MDS. It is important to take the occupational history into account, especially in elderly patients, because in the case of exposure to benzene, for example as a painter/finisher or petrol pump attendant, MDS may be regarded as an occupational disease. The first step should be a microscopic examination of the blood to evaluate single cell morphology, since signs of granulocytic dysplasia, such as hypogranulation or pseudo-Pelger–Huët cells, may be indicative of MDS. Bone marrow cytology and bone marrow histology are mandatory. Bone marrow cytology by definition shows at least 10% cells with impaired differentiation/maturation in one, but in most cases two or all three myeloid cell lines (14). Chromosomal analysis is required for diagnostic and prognostic reasons.

Box 1. Diagnosis of myelodysplastic syndromes/neoplasms (12, 15).

Peripheral blood (mandatory)

• White blood cell count; possibly <4000/µL

• Platelet count, possibly <100 000/µL

• Hemoglobin, almost always <12 g/dL in females, <13.5 mg/dL in males

• Reticulocyte count; usually—but not always—reduced

• Manual differential blood count (neutrophil granulocyte count, signs of dysplasia, blast percentage)

• LDH U/L (levels above normal are indicative of an unfavorable prognosis)

• Ferritin µg/L, possibly elevated

• Erythropoietin level, often increased

• Blood typing, in case transfusions are required

• Not mandatory: HLA typing and CMV status, if eligible for allogeneic stem cell transplantation

• Not mandatory: WT1 expression (if >50 indicative of a poor prognosis)

Bone marrow (mandatory)

• Cytology with staining for iron, POX and esterase staining (extent of dysplasia, blast percentage)

• Histology of a trephine biopsy (cellularity, fibrosis)

• Chromosomal analysis with analysis of 25 metaphases (chromosomal aberrations); complemented by FISH, in individual cases

• Mutation analyses (important genes: TP53, MLL, ETV6, IDH2, CBL, SF3B1, JAK2, ASLX1, RUNX1, SRSF2, U2AF1, DNMT3A, ZRSE2, EZH2, NRAS, KRAS, PDGF-a/b)

• Not mandatory: immunophenotyping

FISH, fluorescence in situ hybridization (FISH); human leukocyte antigen; LDH, lactate dehydrogenase; WT1, Wilms’ tumor 1

Table 1 shows the proposals of the current WHO classification. What is new is that two groups of MDS types are distinguished. One group is classified according to morphology—in this case primarily using the blast percentage which is relevant for prognostication, but MDS with bone marrow fibrosis is now also included in this group due to its prognostic significance (15, 16). The second group is classified on the basis of molecular cytogenetics. In this group, specific genetic alterations determine how the disease is classified. These changes include MDS with deletion (5q), with SF3B1 gene mutation and with bi-allelic TP53 alterations (17– 18). The same classification applies to therapy-related MDS (19). Another international group has proposed a similar classification that less clearly sets out the distinction of MDS from acute leukemias (20).

All defined subgroups carry prognostic significance (extent of blast excess, fibrosis, dysplasia signs, and genetic alterations). On the one hand, their relevance results from the extent of bone marrow insufficiency with increased risk of infections and bleeding, and on the other hand, from factors that increase the risk of AML development/progression of the disease (21). Consequently, there are significant differences in prognosis between these subgroups (16– 18) (Figure 1).

eFigure 1.

Survival curves of the different risk groups according to the IPSS-R. Mean survival of all patients 34 months, mean survival of IPSS-R risk groups: blue: “very low”: 98 months, green: “low“: 61 months, red: “intermediate“: 31 months, orange: “high“: 23 months, brown: “very high risk”: 10 months, p<0.00005, (n= 2694, data from the Düsseldorf MDS Registry).

Thus, more than ever before, close cooperation between cytomorphology, genetics, and pathology is required in the diagnostic workup. The preparation of an integrated report on the findings with comments, taking into account all the methods used, is crucial to ensure the treating hematologist has comprehensive information available.

Prognostication

In advanced MDS in particular, the major causes of death—i.e., infection, hemorrhage, and development of acute myeloid leukemia—are directly related to the disease (21). Numerous biological (e1) and patient-related (22) prognostic parameters have been identified and prognosis scores have been developed (23– 25). Over the last decade, the Revised International Prognostic Scoring System (IPSS-R) has proven to be a robust prognostication tool (eTable 1, eFigure 1, eFigure 2) (26, e2). This score is based on the extent of cytopenia, bone marrow blasts and chromosomal findings; it defines five risk groups. What is new is the additional consideration of results of mutation analyses obtained in the Molecular International Prognostic Scoring System (IPSS-M) in addition to the IPSS-R. The IPSS-M is a regression model solely designed for web-based use; it divides the patients into six categories that are distinct from one another. When weighting somatic mutations, their prognostic significance is taken into account, as well as the number of mutated genes (etable 2). The more complete the information on mutations, the more accurate the prognostic predictive power of the model. Based on 2957 patients, this score was developed with substantial involvement of German MDS centers. As a general rule, most mutations—with the exception of the SF3B1 mutation—have an unfavorable impact on prognosis. This means that such patients must be assigned to a higher risk category and, consequently, may need the therapy indicated for this risk group. In light of the above, screening for somatic mutations is mandatory and the IPSS-M should be used whenever possible and deemed appropriate, taking into account the higher median age of the patient population and the assessed fitness for treatment.

Table 2. Most important side effects of treatment options for patients with myelodysplastic syndrome.

Substance/therapy	Most important side effects
Erythropoietin	– Hypertension
Iron chelation	– Renal failure – Gastrointestinal intolerance
Lenalidomide	– Deterioration of blood count – Thrombosis – Polyneuropathy
Luspatercept	– Fatigue – Gastrointestinal intolerance – Hypertension
TPO analogs	– Thrombotic/thromboembolic events – Headache
Anti-thymocyte globulin	– Allergic reactions – Immunosuppression
Hypomethylating substances	– Blood count deterioration – Infection – Local reactions with s.c. administration
Venetoclax	– Blood count deterioration
Allogeneic peripheral hematopoietic stem cell transplantation	– Life-threatening infections/hemorrhage – Graft-versus-host disease – Toxicity of therapy

eFigure 2.

Cumulative risks for AML transition of the various risk groups according to IPSS-R, blue: “very low”: green: “low“, red: “intermediate“, orange: “high“, brown: “very high“, p<0.00005 (n = 2694, data from the Düsseldorf MDS Registry). AML, acute myeloid leukemia; MDS, myelodysplastic syndromes

eTable 2. Important somatic mutations in myelodysplastic syndromes.

Function	Gene	Prognosis	Approx. percentage
Splicing	SF3B1	Good	15–30%
	SRSF2	Poor	5–10%
	USAF1	Poor	5–10%
	ZRSR2	Indifferent	5%
Transcription factor	RUNX1	Poor	5–10%
	TP53	Poor	5–10%
	BCOR	Poor	5%
	ETV6	Poor	3%
Methylation	DNMT3A	Poor	5–10%
	TET2	Indifferent	15–25%
Histone modification	IDH1/IDH2	Indifferent	5%
	ASXL1	Poor	10–20%
	EZH2	Poor	3–5%
	MLL	Poor	3%
Signaling	NRAS/KRAS	Poor	5–10%
	CBL	Poor	5%

Care and treatment

Initially, a watch-and-wait approach or supportive treatment are indicated for a large proportion of MDS patients who are not classified as high-risk MDS at the time of first diagnosis. Supportive interventions include replacement of blood products, prevention and treatment of infections and, where necessary, erythropoietin replacement therapy.

Especially for low-risk MDS, standardized instruments for quality of life assessment are valuable tools that also allow the treating physician to evaluate treatment success and burden, including supportive interventions. Moreover, quality-of-life-associated factors, such as fatigue, were found to have prognostic relevance. MDS-specific scoring systems (QOL-E, QUALMS) have been developed in addition to well-validated quality-of-life (QoL) instruments, such as the EQ-5D or EORTC-QLQ-C30, but still require further intensive validation (28).

Since over 80% of those affected receive regular supportive red blood cell transfusions over the course of their disease and the human body lacks the ability to excrete iron, transfusion-related iron overload is common and may result in heart failure, cardiac arrhythmias, and other organ damage (29). Therefore, if serum ferritin levels exceed 1000 ng/mL and the patient is transfusion-dependent, chelation therapy should be started to at least mitigate iron overload toxicity. The only available phase III study on iron chelation showed an improvement in prognosis with such therapy (e5, e6). In addition, blood counts improved in about 10–15% of patients and infections were found to be delayed (e7, e8).

Based on data from a double-blind multicenter randomized controlled phase III study, epoetin-α was approved for transfusion-dependent patients without excess blasts and endogenous erythropoietin levels <200 ng/mL. 85% and 68% of MDS patients with moderate transfusion requirements, classified as “very low risk” and “low risk”, respectively, according to IPSS-R, respond to this treatment after a few weeks and may remain transfusion-free for years with therapy (e9, e10).

Transfusion-dependent patients with isolated deletion (5q) and no excess blasts can be treated with lenalidomide, an immunomodulatory agent. The only prospective multicenter phase II study evaluating this indication, the LE-MON-5 trial, showed that approximately two-thirds of patients become transfusion-free within four months (30) and that lenalidomide does not promote progression to AML. During the median follow-up period of 20 months, 73% of these patients did not require transfusion. Determining clone size by fluorescence in situ hybridization (FISH) in peripheral blood significantly helped to establish molecularly guided therapy (31) and to allow long breaks in therapy once transfusion-free status was achieved. Prior to initiation of therapy, screening for TP53 mutation should be performed, as in these cases a more aggressive course of the disease may be observed.

Luspatercept, a TGF-ß ligand trap, has recently been approved for the treatment of transfusion-dependent patients without excess blasts but with a ring sideroblastic phenotype and/or detection of an SF3B1 mutation. It achieves transfusion-free status in 40% of patients. The agent was evaluated by the German MDS Study Group in a multicenter phase II study (32, e11). Thrombopoietin analogs may be used on a case-by-case basis for patients with thrombocytopenia to avoid transfusions of platelet concentrates and to reduce the risk of bleeding, in line with phase II data (e12– e13). Similarly, immunosuppressive therapy with anti-thymocyte globulin (ATG) can be used to improve hematopoiesis in patients with hypoplastic MDS on a case-by-case basis (e14).

Numerous new substances are being evaluated in clinical trials (www.D-MDS.de) (e15). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is currently the only therapy with curative potential. If an HLA-identical sibling or unrelated donor can be identified, allogeneic stem cell transplantation is performed after prior conditioning chemotherapy, which is bone marrow toxic and destroys the patient‘s own diseased hematopoietic stem cells, with the goal of achieving a graft-versus-leukemia (/MDS) effect through the transplanted immune system. Apart from acute toxicity and the risks associated with the aplasia phase after chemotherapy (especially infections, bleeding), the risk of immune diseases, which constitute a distinct clinical entity as graft-versus-host disease (GvHD), and the risk of an MDS relapse are the main factors in the further course of the disease.

When establishing the indication for allogeneic hematopoietic stem cell transplantation (alloHSCT), it is important to include disease factors as well as patient and therapeutic factors in the decision-making process. Since alloHSCT is still associated with high toxicity and consequently significant treatment-related morbidity and mortality (2-year non-relapse mortality rate of 16%) (33), primarily patients with high-risk MDS should be evaluated for this type of treatment. In individual cases, patients classified as low risk according to IPSS-R/M may also benefit from alloHSCT, if they are exposed to a high risk due to severe thrombocytopenia or neutropenia (35). It is important to note that, while alloHSCT is the only hope of cure for patients with high-risk MDS, genetic factors and/or somatic mutations, such as RUNX and TP53, which are associated with an unfavorable prognosis, still have an impact on prognosis even after alloHSCT, because post-transplant relapses are significantly more likely among those patients—for example, 61% in the 5-year estimate (33, 34).

Rather than age, comorbidities such as organ failure or chronic infections, are critical factors driving treatment-related mortality in patients with alloHSCT. Older patients are typically treated with a conditioning regimen, i.e. chemo-/immunotherapeutic agents +/- total body irradiation (TBI) administered in preparation for transplantation. In this setting, a less intensive regimen is used to reduce treatment-related mortality (TRM). In retrospective studies, however, reduced-intensity conditioning was usually associated with an increased likelihood of relapse (e16). In the absence of myeloablative conditioning, especially high-risk patients relapse significantly more frequently. Consequently, conditioning therapy should be chosen to be as intensive as is deemed acceptable in the individual patient (33, 36).

The transplant process itself consists of an intensive early phase of about six weeks, during which patients are cared for in a specialized transplant unit, and a later outpatient monitoring phase of about two years, also with close support in a specialized center. During this late phase, impending complications, such as graft-versus-host disease and infections, should be detected and treated as early as possible, and the success of therapy should be continuously monitored for minimal residual disease by means of complex diagnostic tests (for example, molecular genetic analyses). The fact that MDS relapse after alloHSCT can be successfully treated in 29–71% of cases by early therapy with hypomethylating agents and donor lymphocytes highlights the relevance of minimal residual disease monitoring (37, 38).

Pre-transplant induction chemotherapy or 5-azacytidine therapy to reduce malignant cells has long been considered indispensable, but frequently achieves disease stabilization at most (e17, e18). Studies have shown that this strategy often selects resistant MDS clones that later cause resistant relapses (e19, e20). In addition, more than 30% of these patients develop complications or experience disease progression during pre-transplant therapy, rendering transplantation impossible. Therefore, it is justified in patients with stable MDS disease to adopt an observation-only approach during the donor search and then perform an early, primary alloHSCT (39). Retrospective studies showed that post-transplant relapses can be treated very successfully, especially in this setting (9).

If a patient is not eligible for allogeneic stem cell transplantation, the hypomethylating agent 5-azacytidine can be used. In a randomized controlled phase III study, a survival benefit of about ten months was observed with 5-azacytidine treatment (e21). About half of the patients respond to this treatment at least with an improvement in blood counts, and in some cases also with a reduction in blast percentage. A minimum treatment duration of 4–6 months is required. Patients with good response should continue 5-azacytidine treatment to stabilize its success. Unfortunately, as yet, no robust disease biology-related predictive parameters are known that would allow prediction of treatment success (e22). Various mechanisms of resistance can lead to a loss of efficacy over the course of treatment (e23). Adding the bcl-2 inhibitor venetoclax, already approved for acute myeloid leukemia (AML), appears to improve speed/duration of response, remission rate, and prognosis in patients with high-risk MDS (e24).

New agents and combination therapies are currently undergoing clinical trials in patients with high-risk MDS (CPX351, venetoclax, magrolimab, sabatolimab, etc.).

Treatment of high-risk patients with classical induction chemotherapy, as used in AML, can no longer be recommended because remission rates are low, remission duration is short, and long-term outcomes are extremely disappointing (e25). eFigure 3 shows the survival curves of high-risk patients (IPSS-R risk groups “intermediate”, “high“ and “very high“) by treatment. Patients receiving supportive therapy alone have a mean survival of only 18 months; therapy with 5-azacytidine improves prognosis by a median of six months, but only those who could undergo alloHSCT have a significantly better long-term prognosis.

Figure 2 and Figure 3 show updated treatment algorithms for patients with low risk and high risk, respectively; Table 2 highlights important side effects. It is useful to perform a detailed diagnostic work-up, including a molecular genetic analysis, to be able to offer the most appropriate therapy to each individual patient, considering new prognostic tools (IPSS-M) and in some cases new targeted treatment strategies. Over the course of the disease of an individual MDS patient, the indication for treatment may change or existing therapies may be switched. Moreover, approved treatment options are often exhausted over the course of the disease. These patients, in particular, can benefit from being seen in an MDS center, where new agents or combination therapies are being evaluated in clinical trials. We go to great lengths to design studies that address the clinical needs of as many patients as possible. Unfortunately, inappropriate inclusion and exclusion criteria mean that only a minority of patients are eligible for participation in a great number of clinical trials (40). The German MDS study group coordinates clinical trials for this purpose. In addition, there is close cooperation between the centers, numerous hospitals, medical care centers (MVZs) and hematology practices within the framework of the MDS registry funded by German Cancer Aid and the MDS Biobank in Düsseldorf which provides data and material for numerous scientific projects.

Table 1. Classification of myelodysplastic syndromes (MDS) as proposed by the WHO (15).

	Blast percentage	Banding cytogenetics	Mutations
MDS with defining genetic abnormalities
MDS with low blasts and isolated deletion (5q)	<5% bone marrow; <2% blood	Deletion (5q) isolated, or with 1 other abnormality except monosomy 7 or deletion (7q)	SF3B1 possible
MDS with low blasts and SF3B1 mutation*1		No deletion (5q), no monosomy 7, no complex aberrant karyotype	SF3B1
MDS with biallelic TP53 inactivation	Any	Typically complex aberrant	or more TP53 mutations, or 1 mutation plus evidence of copy number loss of TP53.
MDS defined by morphology*2
MDS with low blasts	<5% bone marrow; <2% blood
MDS, hypoplastic*3
MDS with excess blasts
MDS with excess blasts-1	5–9% bone marrow and/or 2–4% blood
MDS with excess blasts-2	10–19% bone marrow and/or 5–19% blood
MDS with fibrosis	5–19% bone marrow; 5–19% blood

*¹ Detection of ≥ 15% ring sideroblasts can substitute for detection of an SF3B1 mutation

*² ≥ 10% signs of dysplasia in at least one cell line

*³ ≥ 25% bone marrow cellularity, age-adapted –

Figure 1.

Figure 1

Mean survival time according to WHO subtype in years; MDS, myelodysplastic syndrome

Box 2. Parameters used to apply the IPSSmoL and entered into the web-based calculator.

Data on bone marrow blasts, platelets, hemoglobin, chromosomal risk group, number of TP53 mutations, and loss of TP53 heterozygosity are mandatory; additional data make the estimation of the model more robust and valid. The IPSS-M is used to calculate the risk groups “very low”, “low”, “moderate low”, “moderate high”, “high”, and “very high”.

Clinical parameters

• Bone marrow blasts in % (mandatory)

• Platelets × 100 000/µL (mandatoty)

• Hemoglobin g/dL (mandatory)

• Neutrophils × 100 000/µL

• Age

Chromosomal findings (according to the IPSS-R)

Mandatory:

Very good (-Y, del [11 q])

Good (normal, del [5q], del [12p], del [20q], double clone with del [5q] except chr 7)

Intermediate (del [7 q], + 8, + 19, i[17 q], other single or double independent clones.)

Poor (- 7, inv[3]/t[3q]/del [3 q], double clone with –7/del [7q], complex [3 aberrations])

Very poor (complex >3 aberrations)

Molecular cytogenetic findings

Mandatory:

• Number of TP53 mutations (0 versus 1 versus 2 or more)

• Loss of heterozygosity of TP53 (yes or no)

• MLL-PTD (mutated versus not mutated versus unknown)

• FLT3 (ITD or TKD) (mutated versus not mutated versus unknown)

Genes with individual weighting

Mandatory:

• ASXL1 (mutated versus not mutated versus unknown)

• CBL (mutated versus not mutated versus unknown)

• DNMT3A (mutated versus not mutated versus unknown)

• ETV6 (mutated versus not mutated versus unknown)

• EZH2 (mutated versus not mutated versus unknown)

• IDH2 (mutated versus not mutated versus unknown)

• KRAS (mutated versus not mutated versus unknown)

• NPM1 (mutated versus not mutated versus unknown)

• NRAS (mutated versus not mutated versus unknown)

• RUNX1 (mutated versus not mutated versus unknown)

• SF3B1 (mutated versus not mutated versus unknown)

• SRSF2 (mutated versus not mutated versus unknown)

• U2AF1 (mutated versus not mutated versus unknown)

Facultative:

Number of mutations among the following genes (is calculated)

• BCOR (mutated versus not mutated versus unknown)

• BCORL1 (mutated versus not mutated versus unknown)

• CEBPA (mutated versus not mutated versus unknown)

• ETNK1 (mutated versus not mutated versus unknown)

• GATA2 (mutated versus not mutated versus unknown)

• GNB1 (mutated versus not mutated versus unknown)

• IDH1 (mutated versus not mutated versus unknown)

• NF1 (mutated versus not mutated versus unknown)

• PHF6 (mutated versus not mutated versus unknown)

• PPM1D (mutated versus not mutated versus unknown)

• PRPF8 (mutated versus not mutated versus unknown)

• PTPN11 (mutated versus not mutated versus unknown)

• SETBP1 (mutated versus not mutated versus unknown)

• STAG2 (mutated versus not mutated versus unknown)

• WT1 (mutated versus not mutated versus unknown)

Figure 2.

Therapy algorithm for patients with myelodysplastic syndrome and very low, low, or intermediate risk: approved = gray (erythropoietin-alpha, Exjade, lenalidomide, luspatercept)

EPO, erythropoietin

Figure 3.

Therapy algorithm for patients with myelodysplastic syndrome and intermediate risk (int-2), high risk or very high risk: approved gray (5-azazytidine,9 allogeneic stem cell transplantation)

eTable 1. Definition of the Revised International Prognostic Scoring System (IPSS-R) (26).

	0	0.5	1	1.5	2	3	4
Karyotype	*1		*2		*3	*4	*5
Blasts (%)	≤ 2		> 2 ≤ 5		5–10	> 10
Hb concentration (g/dL)	≥ 10		8 10	< 8
Platelets (/nL)	≥ 100	50 ≤ 100	< 50
Neutrophils (/nL)	≥ 0.8	< 0.8
Risk score	Points		Median survival (years)
“very low risk”	≤ 1.5		9.00
“low risk”	2–3		5.63
“intermediate risk”	3.5–4.5		2.63
“high risk”	5–6		1.28
“very low risk”	> 6		0.85

*¹ Very good (-Y, del[11q])

*² Good (normal, del[5q], del[12p], del[20q], double clone with del[5q] except chromosome 7)

*³ Intermediate (del[7q], +8, +19, i[17q], other single or double clones)

*⁴ Poor (-7, inv(3)/t(3q)/del(3q), double clone with –7/del(7q), complex with max. 3 aberrations)

*⁵ Very poor (complex with more than 3 aberrations)

eFigure 3.

Survival curves of patients with “intermediate”, “high” and “very high risk” after IPSSR, according to therapy, mean survival time of all patients 20 months, mean survival time with “best supportive care” 18 months, with induction chemotherapy 18 months, with therapy with 5-azacytidine, 24 months and with allogeneic stem cell transplantation 96 months, p<0.0005 (n = 887, data from the Düsseldorf MDS Registry). BSC, best supportive care; MDS, myelodysplastic syndromes

Questions on the article in issue 12/2023:

Myelodysplastic Syndromes

New Methods of Diagnosis, Prognostication, and Treatment

The submission deadline is 23 March 2024. Only one answer is possible per question. Please select the answer that is most appropriate.

Question 1

In what age range is the median age of onset for myelodysplastic syndromes?

1. 40–45 years

2. 50–55 years

3. 60–65 years

4. 70–75 years

5. 80–85 years

Question 2

Elevation of which of the following blood parameters (from peripheral blood) may indicate the presence of myelodysplastic syndrome/myelodysplastic neoplasia?

1. White blood cell count

2. Hemoglobin

3. Ferritin

4. Reticulocyte count

5. Platelet count

Question 3

From what percentage of cells with signs of impaired differentiation or maturation in bone marrow cytology is the diagnosis of MDS assumed by definition?

1. 5%

2. 10%

3. 20%

4. 35%

5. 70%

Question 4

For which genotype does the text describe the option of treatment with lenalidomide?

1. Isolated deletion 5q

2. Isolated SF3B1 mutation

3. Isolated TP53 mutation

4. Isolated NRAS mutation

5. Isolated deletion KRAS

Question 5

Median survival is less than 2 years for which of the following WHO subtypes of MDS?

1. MDS IB1

2. Deletion 5q

3. Hypoplastic MDS

4. MDS with ring sideroblasts

5. Biallelic TP53 mutation

Question 6

Of the following genes, which is an exception in that it is associated with a comparatively favorable prognosis according to the IPSS-M score?

1. NRAS

2. RUNX1

3. USAF1

4. SF3B1

5. CBL

Question 7

In which situation does the text recommend starting chelation therapy?

1. Whenever a transfusion therapy is started

2. In patients with serum ferritin levels >1000 ng/mL

3. In patients with erythropoietin replacement therapy

4. In patients treated with luspatercept

5. In patients with low red blood cell count

Question 8

In the article, the use of which drug is described to improve prognosis in patients with high-risk MDS who are not eligible for allogeneic stem cell therapy?

1. Lenalidomide

2. Sabatolimab

3. Gefitinib

4. 5-azacytidine

5. Tamoxifen

Question 9

According to the text, what percentage of patients with MDS have therapy-related MDS?

1. approx. 0.5%

2. approx. 5%

3. approx. 10%

4. approx. 20%

5. approx. 35%

Question 10

In the text, which substance is mentioned for the treatment of SF3B1 mutations?

1. Lenalidomide

2. Luspatercept

3. Exjade

4. Tamoxifen

5. Cisplatin