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MDS care.³¹

      Gait speed and grip strength are easily obtainable objective measures of physical function that take no more time to measure than a typical vital sign. Gait speed accurately predicts mortality, disability, and hospitalizations across populations worldwide.^32‐34 Recent guidelines by ASCO recommend gait speed as a practical assessment of function and physical performance in older adults with cancer.³⁵ Grip strength is primarily a measure of physical function and is not as well established as gait speed as a marker of frailty, but it may be useful in patients who are in clinics.

      The Short Physical Performance Battery (SPPB) evaluates lower extremity function and predicts future disability, hospitalizations, and mortality among elderly patients with demonstrated reliability across diverse older adult populations. The SPPB comprises a short walk (4 m), repeated chair stands, and a balance test. Each measure is scored ranging from 0 to 4 (0 = unable to complete the test; 4 = highest performance level), with a total summed score ranging from 0 to 12. This test predicts survival and adds explanatory power beyond‐traditional prognostic variables including age, ECOG PS, and cytogenic risk group.³⁶

      However, a comprehensive geriatric assessment (CGA) is considered the standard of care, as recommended by SIOG (International Society of Oncological Geriatrics)³⁷ and recently by ASCO (American Society of Clinical Oncology)³⁵, to identify the patient's fragility and functional reserve. CGA is the only tool that can assess the frailty of elderly cancer patients, predicting the risk of toxicity associated with treatments and the risk of mortality.

      Performing a comprehensive geriatric assessment is now essential to identify problems that are not immediately evident. Numerous studies have shown the ability of the CGA to identify otherwise unknown vulnerabilities; support the decision‐making process of the specialist, oncologist, radiotherapist, or surgeon; estimate the risk of toxicity and prevent it; and preserve the patient’s functional performance.^38‐40

Diagnosis

      Blood and bone marrow examination

      MDS is diagnosed in patients with one or more cytopenias and depends on the finding of dysplastic features within the bone marrow in one or more lineages.

      Complete blood count

Usually, the first clinical sign of MDS is the detection of cytopenias (anaemia, leukopenia, or thrombocytopenia) in a complete blood count. For MDS criteria, the cytopenias must be persistent and under specific thresholds (Table 26.1).

Table 26.1 Cytopenia thresholds according to the WHO 2016 Classification.

Hemoglobin	<10 g/dL
Platelets	<100 × 109/L
Absolute neutrophil count	<1.8 × 109/L

      Peripheral blood smear

      A peripheral blood smear can show morphological changes of cells: in peripheral blood, we can observe dysgranulopoiesis, nuclear abnormalities, pseudo‐Pelger‐Huet cells, inclusions in erythrocytes (such as Howell‐Jolly or Pappenheimer bodies or basophilic stippling), and platelet anisocytosis (typically giant or agranular platelets).

      Other useful parameters of peripheral blood

      To proceed with MDS diagnosis, it is important to exclude other diseases with similar peripheral blood characteristics. It is important to evaluate the vitamin and iron assessment together with erythropoietin levels and hepatic, renal, and thyroid function.

      Bone marrow analysis

      To make the diagnosis, a bone marrow aspirate and biopsy are required. An aspirate is necessary to evaluate morphology, quantify the number of myeloblasts, and assess for cytogenetic abnormalities. A core bone marrow biopsy is used to assess the bone marrow cellularity, which is typically hypercellular and indicative of ineffective hematopoiesis in the setting of peripheral cytopenias.

      The morphological features of red cell precursors in the bone marrow aspirate include megaloblastic (asynchronous maturation of the nucleus and cytoplasm), binucleate or multinucleated cells, and ring sideroblasts. Ring sideroblasts are red cell precursors with iron‐laden mitochondria and are defined by the presence of five or more Prussian Blue‐staining iron granules encircling more than one‐third of the nucleus in more than 15% of the erythroblasts. Erythroid hyperplasia may also be prominent and is associated with ineffective erythropoiesis that is a hallmark of MDS.

      Abnormalities in the myeloid series include a predominance of immature myeloid cells and hypogranulation and hypolobulation of the nucleus in mature granulocytes. A classic finding is the presence of pseudo‐Pelger–Huet cells, which are granulocytes with a bilobed nucleus in a pince‐nez configuration. A required feature in the bone marrow of MDS patients is the presence of >5% myeloblasts: the proportion of myeloblasts has both diagnostic and prognostic information and is important in differentiating AML from MDS.

The megakaryocytes may likewise be dysplastic and may have not only a quantitative but also a qualitative defect. In the bone marrow, the megakaryocytes may be small and hypolobulated.

      Differential diagnosis

      Dysplasia in the bone marrow is not sufficient to establish the diagnosis of myelodysplasia. Deficiencies of vitamin B12 and folate, hypothyroidism, viral infections such as Epstein–Barr and the human immunodeficiency virus, and exposure to antibiotics and other chemicals such as ethanol, chemotherapy and benzene can result in dysplasia. These causes must be ruled out systematically by a careful history and physical and laboratory examination.

      Cytogenetics

      A critical component of the bone marrow aspiration is the cytogenetic examination of the bone marrow, which may help to establish the diagnosis and yields important prognostic information. It is well established that cytogenetic patterns are very heterogeneous in MDS.⁴¹

      Roughly 60% of patients with MDS have a normal karyotype, but the presence of a common cytogenetic abnormality may establish the diagnosis in difficult cases.⁴² One series found that cytogenetic abnormalities were more common in the advanced stages of MDS compared with the less‐advanced MDS subtypes.⁴³

      The more common abnormalities are trisomy 8 and deletions of the long arms of chromosomes 5, 7, 11, 13, and 20. Complex karyotypes, defined as three or more cytogenetic abnormalities, are found in 15% of cases and confer a poor prognosis.^41,43 Deletion of 5q is seen commonly in patients with refractory anaemia and represents a distinct clinical syndrome, the ‘5q syndrome’.

      Therapy‐related MDS is also associated with specific chromosomal abnormalities. In particular, partial or complete loss of chromosome 5 or 7 has been seen after exposure to alkylator therapy.

      Cytogenetics is not only strongly correlated with the calculation prognosis but also important for the selection of the most effective therapy; thus, a complete bone marrow karyotype remains the standard workup evaluation procedure of the patient with MDS.⁴⁴ Cytogenetic prognostic groups have been proposed in the revised international score (IPSS‐R) scheme, which includes 5 different subgroups with 20 different alterations.^44,45

      Other genetic events

      Over the past few years, our understanding of the genetic basis for MDS has expanded significantly. The mutations observed in MSD involve genes that encode diverse proteins

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