three times higher. This increase is probably due in part to an increasing population of people over age 65 and increased recognition and diagnosis of the disease by haematologists and oncologists with the development of more effective therapies.
The age‐adjusted incidence of MDS is slightly higher among males than females. However, these are likely underestimations of this disease's true incidence due to the underdiagnosis of MDS in the past.
There are several well‐known risk factors for the development of MDS, including exposure to organic solvents (e.g. benzene), ionizing radiation, and prior chemotherapy (e.g. alkylating agents). Inherited genetic abnormalities (e.g. trisomy 21, Fanconi anaemia, Bloom syndrome, ataxia‐telangiectasia) and other benign hematologic diseases (e.g. paroxysmal nocturnal hemoglobinuria, congenital neutropenia) have also been associated with MDS.
The incidence of therapy‐related myelodysplasia is also increasing. Therapy‐related MDS can result from prior exposure to ionizing radiation or chemotherapy. Prior exposure to alkylating agents is associated with the highest risk of MDS and has very distinct cytogenetic abnormalities, such as loss of the long arm of chromosomes 5 and/or 7. The risk for developing therapy‐related MDS or AML has been described in long‐term survivors of cancers treated with semustine (methyl‐CCNU). The actuarial risk is between 6 and 9% in patients treated for Hodgkin’s disease and 17% in patients treated for multiple myeloma. The risk of developing MDS increases with the use of regional radiation therapy following treatment for common cancers such as breast cancer, small cell lung cancer, and testicular cancer. Topoisomerase II inhibitors, such as epipodophyllotoxins and anthracyclines, have also been associated with therapy‐related AML, but usually without an MDS prodrome, and commonly involve chromosomal abnormalities such as 11q23, 3q26, and 21q22.15
The clinical presentation of MDS is varied. Symptoms for the most part are non‐specific and depend on the number and severity of cytopenias present. The majority of patients with MDS have a macrocytic anaemia with or without additional cytopenias. Others present symptoms or complications resulting from a previously unrecognized cytopenia: dyspnoea on exertion, fatigue, lethargy, malaise, dizziness, and even angina.2 Neutropenic patients may develop severe systemic infections, and infection represents a primary cause of death in many cases of MDS. The increased infectious risk may be a result of neutrophil dysfunction secondary to impaired chemotaxis and/or microbial killing.16,17 T‐cell function is thought to remain intact, and therefore patients with MDS less commonly develop viral or mycobacterial infections in the absence of treatment with immunosuppressive agents.16 Other symptoms may include easy bruising or bleeding, a common manifestation of thrombocytopenia and dysfunctional platelets.
The physical findings of MDS are likewise non‐specific and usually reflect underlying cytopenias if present. Of note, patients with chronic myelomonocytic leukaemia (CMML) may have splenomegaly, an unusual finding in patients with other subtypes of MDS.
Elderly patients and risk assessment
Prognosis and treatment decisions in MDS are guided by a patient's estimated disease risk. Several risk scores have been developed to predict the natural history of the disease, specifically length of survival and risk of progression to AML in the absence of intervention. These risk scores integrate disease features at diagnosis, including cytopenias, presence of excess bone marrow myeloblasts, and type of cytogenetic abnormalities.18
Given the older age of the MDS population, it is critical to consider the impact of comorbidity and frailty. The impact of comorbidity on MDS prognosis is of practical importance to the treating oncologist. Several studies have recently defined the impact of comorbidity on prognosis in MDS patients and collectively generated a body of work demonstrating that increased comorbidity negatively impacts survival (even accounting for traditional MDS risk factors) and that integration of comorbidity assessment to traditional risk stratification can improve prognostic accuracy.19‐23
Risk stratification for older adults has primarily focused on biology, performance status (Eastern Cooperative Oncology Group [ECOG] or Karnofsky) and chronological age. Older chronologic age has been a consistent predictor of poor outcomes, contributing to the controversy surrounding optimal treatment strategies for older adults. Chronologic age, however, is a surrogate marker for specific impairments that increase vulnerability to treatment toxicity and poor outcomes. To date, few studies have focused on the measurement of underlying impairments that better reflect physiologic age and reserve capacity during treatment.24,25
Frailty is a general state of physiologic decline that results in a ‘state of high vulnerability to adverse health outcomes’ in the face of medical stressors events.26 Frailty may be particularly prevalent among older patients with hematologic malignancies; more than half of them have evidence of malnutrition, and more than a third have impaired physical function.27 Moreover, hematologic malignancies and their treatment can lead to frailty in a patient of any age. Frailty is associated with increased chemotherapy‐related toxicity, poor response to therapy, and mortality in solid and hematologic malignancies.28,29 Accordingly, leading professional organizations, such as the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network, now recommend that geriatric and frailty assessments must be incorporated into the routine care of older patients with cancer.30
While challenges exist to incorporating frailty assessment into clinical oncology practice, routine frailty screening has been shown to be feasible for patients with MDS. Such screening enhances the ability of oncologists to make appropriate MDS treatment recommendations. In addition, routine frailty assessment by oncology providers can identify patients who would benefit from comprehensive geriatric assessment (CGA) and management with a geriatrician concurrent with their 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
