Overview of the treatment of myelodysplastic syndromes

INTRODUCTION — Myelodysplastic syndromes (MDS) comprise a group of hematologic malignancies characterized by clonal hematopoiesis, one or more cytopenias (ie, anemia, neutropenia, and/or thrombocytopenia), and abnormal cellular maturation. Patients are at risk for symptoms related to anemia, infection, and bleeding, and they have variable rates of transformation to acute myeloid leukemia (AML). (See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)".)

This topic will provide an overview of the treatment of MDS.

Detailed discussions of the following issues are presented separately:

●(See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)".)

●(See "Prognosis of myelodysplastic neoplasms/syndromes (MDS) in adults".)

●(See "Myelodysplastic syndromes/neoplasms (MDS): Management of hematologic complications in lower-risk MDS".)

●(See "Treatment of lower-risk myelodysplastic syndromes (MDS)".)

●(See "Treatment of high or very high risk myelodysplastic syndromes".)

●(See "Treatment of high or very high risk myelodysplastic syndromes", section on 'Allogeneic HCT'.)

MDS CATEGORY — Prior to choosing a course of treatment, the diagnosis of MDS must be verified, other conditions in the differential diagnosis should be excluded, the World Health Organization (WHO) category should be determined, and a prognostic risk category assigned.

Verify the diagnosis — Prior to choosing a course for management, the diagnosis of MDS must be verified and other disorders in the differential diagnosis excluded.

●Bone marrow evaluation – A bone marrow specimen is required for the diagnosis of MDS. The specimen should be analyzed for morphology, immunophenotype, cytogenetics, and molecular findings, as described separately. (See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)", section on 'Bone marrow examination'.)

●Diagnosis – The diagnosis of MDS requires: cytopenia in at least one blood lineage, morphologic dysplasia in ≥10 percent of nucleated cells in at least one lineage, <20 percent blasts in blood and bone marrow, and/or characteristic cytogenetic or molecular findings, without evidence of an alternate cause of these findings. Further details of the diagnosis of MDS are presented separately. (See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)".)

●Exclude other conditions – Other conditions in the differential diagnosis can be excluded by evaluation of the bone marrow specimen, including histology and selected laboratory studies. Other conditions that may resemble MDS include (see "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)", section on 'Differential diagnosis'):

•Cytopenias and/or dysplasia – Nutritional deficiencies (eg, folate, vitamin B12, copper deficiency), medications, toxic exposures (eg, alcohol, heavy metals), infections (eg, HIV, parvovirus B19), autoimmune conditions (eg, systemic lupus erythematosus), or heritable or acquired causes of dysplasia. (See "Approach to the adult with unexplained neutropenia" and "Diagnostic approach to anemia in adults" and "Diagnostic approach to thrombocytopenia in adults".)

•Clonal hematopoiesis – Clonal hematopoiesis of indeterminate potential (CHIP), idiopathic cytopenia of undetermined significance (ICUS), clonal cytopenia of undetermined significance (CCUS), aplastic anemia (AA)/paroxysmal nocturnal hemoglobinuria (PNH). (See "Clonal hematopoiesis of indeterminate potential (CHIP) and related disorders of clonal hematopoiesis" and "Idiopathic and clonal cytopenias of uncertain significance (ICUS and CCUS)".)

•Other myeloid neoplasms – Acute myeloid leukemia (AML), myeloproliferative neoplasms (MPN), MDS/MPN syndromes (eg, chronic myelomonocytic leukemia), myelofibrosis. (See "Acute myeloid leukemia in adults: Overview" and "Clinical manifestations and diagnosis of chronic myeloid leukemia" and "Overview of the myeloproliferative neoplasms".)

MDS classification — MDS should be categorized according to the WHO classification [1,2]. The WHO classification system has replaced the outdated French-American-British (FAB) system. (See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)".)

The WHO classification of MDS is based on the number of cytopenic and dysplastic lineages, percentage of blasts and ring sideroblasts, and cytogenetic findings, as follows:

●MDS with single lineage dysplasia

●MDS with multilineage dysplasia

●MDS with ring sideroblasts

●MDS with isolated del(5q)

●MDS with excess blasts

●MDS, unclassifiable

PROGNOSTIC CATEGORY — Assignment of a risk category is important for sharing prognostic information with the patient and for selecting treatment. We suggest using the revised international prognostic scoring system (IPSS-R) (table 1) (calculator 1) or the original IPSS (table 2) (calculator 2), which are based on the percentage of bone marrow blasts, number and severity of cytopenias, and cytogenetic findings. We categorize patients as follows [3]:

●Lower-risk MDS:

•IPSS-R: ≤3.5 points

•IPSS: ≤1 point

●Higher-risk MDS:

•IPSS-R: ≥4.0 points

•IPSS: ≥1.5 points

Further details of these and other prognostic models are presented separately. (See "Prognosis of myelodysplastic neoplasms/syndromes (MDS) in adults", section on 'IPSS (Original IPSS)'.)

MEDICAL FITNESS — Medical fitness is determined by clinical and laboratory evaluation, performance status, and severity of comorbid conditions. Classification of medical fitness is important for choosing treatment of MDS. In judging medical fitness, it is important to recognize that age, per se, does not determine medical fitness. Additional information for judging medical fitness, especially in older patients, is discussed separately. (See "Pretreatment evaluation and prognosis of acute myeloid leukemia in older adults".)

Clinical and laboratory evaluation — Pretreatment clinical evaluation and laboratory studies should assess the nature and severity of symptoms, degree and complications of cytopenias, and comorbid conditions that may affect treatment.

●Clinical – The clinical evaluation should assess findings related to cytopenias and seek to identify factors that may exacerbate these conditions. This should include assessment of clinical consequences of anemia (eg, dyspnea, weakness, history of transfusions), thrombocytopenia (eg, bleeding, bruising), and neutropenia (eg, recurrent or severe infections). Clinical manifestations of comorbid illnesses, including heart disease, pulmonary processes, and renal impairment should be documented.

●Laboratory studies:

•Complete blood count, differential count, reticulocyte count, prothrombin time (PT), partial thromboplastin time (PTT)

•Electrolytes, renal and liver function tests (including lactate dehydrogenase [LDH])

•Serum iron, total iron-binding capacity, ferritin, vitamin B12, folate

•Serum erythropoietin (EPO)

•Serology for HIV and hepatitis B and C

Fitness assessment instruments — Assessment of medical fitness can be judged by the following instruments:

●Performance status – Eastern Cooperative Oncology Group (ECOG) performance status (PS) scale (table 3) is useful for assessing activities of daily living (ADL).

●Physiologic fitness – We use the Charlson comorbidity index (CCI) (table 4) to assess the severity of comorbid conditions, ADL, physical performance tests, and cognition. Other instruments such as the short physical performance battery (SPPB) are also acceptable.

For some older patients, a comprehensive geriatric assessment and geriatric consultation may aid assessment of the medical fitness, as discussed separately. (See "Pretreatment evaluation and prognosis of acute myeloid leukemia in older adults", section on 'Pretreatment evaluation'.)

Fitness categories — We classify patients according to their medical fitness for treatment, based on PS and physiologic fitness, as described above.

There are no clear distinctions between fitness categories, and some measures of PS or physiologic fitness can apply to different categories of fitness. Chronic comorbid conditions should be weighed more heavily than transient medical complications of the leukemia itself (eg, infection due to neutropenia, heart failure exacerbated by anemia).

●Medically-fit – Medically-fit patients are those who are considered able to tolerate intensive treatment for acute myeloid leukemia (AML), based on both of the following:

•ECOG PS (table 3): 0 to 2

•CCI (table 4): 0 to 2

●Medically-unfit, but not frail – Patients who are medically-unfit but not frail are unlikely to tolerate intensive treatments because of impaired PS or comorbid conditions. This category includes a broad range of physical function; some have only modest, recent, or transient impairment of functional status, while others have substantial comorbid illnesses, cognitive impairment, or other conditions that may affect their ability to tolerate treatment.

We judge patients to be medically-unfit but not frail if either of the following applies:

•ECOG PS (table 3): 3

•CCI (table 4): 3

●Frail – Frail patients are those whose debility or comorbid conditions would not permit treatment aimed at modifying the disease course, as reflected by both the following:

•ECOG PS (table 3): >3

•CCI (table 4): >3

GOALS OF CARE — Goals of care should be established in discussions between the patient and clinicians at the time of diagnosis and periodically through the course of the disease.

●For most patients with MDS, the goals of care are to lessen symptoms, improve the quality of life, and prolong survival, while minimizing treatment-related toxicity.

●Allogeneic hematopoietic cell transplantation (HCT) is the treatment with the highest potential to cure MDS. However, because of advanced age, comorbid conditions, lack of adequately matched donors, and/or patient preferences, only a small subset of patients with MDS are candidates for allogeneic HCT.

MANAGEMENT — MDS is a heterogeneous disease and treatment should be individualized. We encourage participation in a clinical trial, when possible.

Selection of treatment is influenced by the severity of symptoms and cytopenias, MDS classification, prognostic category, medical fitness, and patient preferences. (See 'Medical fitness' above and 'Prognostic category' above.)

Our approach is similar to that proposed by the MDS Panel for Practice Guidelines of the National Comprehensive Cancer Network (NCCN), British Committee for Standards in Haematology, European Society of Medical Oncology, and the European LeukemiaNet [4-8].

Lower-risk MDS — For patients with lower-risk MDS, we offer treatment based on the severity of cytopenias and symptoms (algorithm 1).

We consider symptomatic patients to manifest any of the following:

●Anemia – Symptoms related to anemia (eg, dyspnea, fatigue, weakness) and hemoglobin (Hb) <10 g/dL

●Thrombocytopenia – Platelets <20,000/microL or excessive bleeding or bruising with platelets <50,000/microL

●Neutropenia – Recurrent and/or severe infections in the setting of persistent absolute neutrophil count (ANC) <500 neutrophils/microL or ANC <1000 neutrophils/microL with recurrent or infections

Asymptomatic — For asymptomatic patients, we generally offer monitoring rather than immediate treatment (algorithm 1), because there is no evidence that early treatment of asymptomatic lower-risk MDS improves long-term survival and deferral of treatment precludes potential treatment-related adverse events.

Asymptomatic patients should be followed expectantly to evaluate the tempo of disease; receive supportive care, if needed (eg, antibiotics for bacterial infections, transfusions for critical cytopenias prior to surgery); and have age-appropriate health maintenance (eg, vaccinations, counseling for smoking cessation, healthy diet, weight control, screening for other cancers). (See "Treatment of lower-risk myelodysplastic syndromes (MDS)", section on 'Asymptomatic patients'.)

Symptomatic — Symptomatic patients with lower-risk MDS are treated according to the severity of cytopenias and symptoms, such as ongoing transfusion requirements, progressive cytopenias, or a declining quality of life.

●Lower-intensity therapies – For most symptomatic patients with lower-risk MDS, we treat with a lower-intensity therapy, supplemented by supportive care as needed. Lower-intensity treatments can lessen symptoms, improve the quality of life, and may lengthen survival, but they are not curative.

The choice of a lower-intensity treatment is guided by which cell lineages are affected, laboratory findings (eg, serum erythropoietin [EPO]), MDS classification (eg, cytogenetic and molecular findings), drug availability, and patient preferences (algorithm 1), as discussed separately. (See "Treatment of lower-risk myelodysplastic syndromes (MDS)", section on 'Symptomatic MDS'.)

Examples of lower-intensity treatments include growth factors (eg, epoetin alfa, thrombopoietin receptor agonists), luspatercept, hypomethylating agents (HMA; eg, azacitidine, decitabine), immunosuppressive therapy, lenalidomide, and targeted agents (eg, IDH inhibitors). These treatments are generally administered in the outpatient setting and they have a low risk of treatment-related morbidity and mortality.

●Intensive treatments – Some patients (typically younger, medically-fit individuals) with more advanced lower-risk MDS or adverse features that are not represented with current scoring systems may choose intensive approaches that can alter the natural history of MDS but are associated with substantial morbidity and mortality. Intensive approaches (eg, intensive remission induction chemotherapy, allogeneic hematopoietic cell transplantation [HCT]) may be selected because the patient places greater value on long-term disease control and the potential for a prompt response than on the treatment-related toxicity and/or mortality. (See "Treatment of high or very high risk myelodysplastic syndromes", section on 'Intensive chemotherapy'.)

●Supportive care alone – Some patients may decline specific treatment for MDS and opt for supportive care alone, based on frailty or personal values and preferences. (See "Myelodysplastic syndromes/neoplasms (MDS): Management of hematologic complications in lower-risk MDS".)

Higher-risk MDS — Treatment choices for patients with higher-risk MDS are informed by medical fitness, pathologic features, and personal values. Assessment of medical fitness is discussed above. (See 'Medical fitness' above.)

Medically-fit — A wide range of treatment options is available to the medically-fit patient with higher-risk MDS. Age, per se, does not govern the choice of treatment, but caution is appropriate when considering intensive approaches for patients ≥75 years, because their benefits and toxicities have been defined primarily in younger patients. We encourage early evaluation by transplant specialists to determine eligibility for allogeneic HCT. (See "Determining eligibility for allogeneic hematopoietic cell transplantation".)

There is no optimal treatment for all medically-fit patients, and the approach varies by institution. The choice of therapy is influenced by adverse pathologic features (eg, TP53 mutation, adverse cytogenetic abnormalities), presence of mutations that are amenable to a targeted agent (eg, IDH inhibitors) (algorithm 2), availability of a stem cell donor and caregiver, and individual values and preferences.

●Intensive treatments – Medically-fit patients may be candidates for intensive remission induction chemotherapy, with or without allogeneic HCT. Intensive treatments that include allogeneic transplantation have the potential to achieve long-term disease-free survival, but they are associated with considerable short-term and long-term toxicity. Discussion of intensive therapies, outcomes, and adverse effects is presented separately. (See "Treatment of high or very high risk myelodysplastic syndromes", section on 'Patients suitable for intensive treatment'.)

●Lower-intensity therapies – Some patients may instead choose lower-intensity therapy (eg, HMA alone or with other agents, targeted agents) (algorithm 1). This approach is associated with more modest toxicity (eg, neutropenic infections) and can provide relief of symptoms, improve the quality of life, and extend survival, but is not curative and does not preclude later use of more intensive approaches. (See "Treatment of lower-risk myelodysplastic syndromes (MDS)", section on 'Symptomatic MDS'.)

Medically-unfit, but not frail — There is no optimal treatment for patients who are medically-unfit, but not frail; this fitness category includes a wide spectrum of patients. Most are treated with lower-intensity therapies, while others may choose supportive care alone. If reduced fitness is disease-related, it may improve with treatment.

Selection of treatment is informed by the patient's goals of care and personal preferences, institutional approach, and genetic features of the MDS cells:

●Management of the patient who is eligible for intensive treatment (eg, intensive remission induction chemotherapy, allogeneic HCT) is discussed separately. (See "Treatment of high or very high risk myelodysplastic syndromes", section on 'Patients suitable for intensive treatment'.)

●For patients who are not candidates or who decline intensive treatments, we favor lower-intensity therapy, with the choice of therapy based on pathologic features, drug availability, and patient preference (algorithm 1). (See "Treatment of lower-risk myelodysplastic syndromes (MDS)", section on 'Lower intensity agents'.)

●Some patients may choose to receive supportive care alone, as described for frail patients.

Frail — Frail patients are unlikely to tolerate treatment other than supportive care. (See "Myelodysplastic syndromes/neoplasms (MDS): Management of hematologic complications in lower-risk MDS".)

RESPONSE ASSESSMENT AND MONITORING — Patients should be evaluated to determine the response to therapy, monitor for disease progression, and assess possible treatment- or disease-related complications. (See "Treatment of lower-risk myelodysplastic syndromes (MDS)", section on 'Monitoring'.)

●Response to therapy – Response to therapy is primarily assessed by alleviation of symptoms, improved blood and/or blast counts, reduced transfusion needs, and improved quality of life. Particularly for patients with higher-risk disease, some clinicians favor assessing response with a bone marrow examination after two to four cycles of therapy, but for patients with lower-risk disease, we generally reserve bone marrow examinations for evaluation of possible disease progression based on an unanticipated deterioration of blood counts or other worrisome clinical findings.

It should be recognized that most patients respond slowly to lower-intensity agents; a meaningful improvement may require three or more months of treatment. Patients should remain on therapy for as long as they are deriving benefit and not experiencing significant adverse effects. For patients who experience significant adverse effects, we judiciously reduce the drug dose or offer brief treatment delays rather than abandoning the treatment, especially if there is evidence of a response.

●Monitoring – The schedule and protocol for follow-up should be individualized according to the severity of symptoms and cytopenias and concerns on the part of the patient and clinician.

We perform a focused history and physical examination, complete blood count with differential, and other laboratory studies, as clinically indicated. Patients should be educated regarding potential complications of MDS and asked to call the office promptly if they develop a fever or bleeding.

TREATMENT OF RECURRENT OR REFRACTORY DISEASE — For patients who do not respond adequately to initial therapy or have worsening symptoms or disease progression after an earlier response, we select subsequent management based on prior therapy.

●Disease re-evaluation – The extent of re-evaluation for a patient who relapses after an initial response to therapy should be guided by the clinical presentation. For patients who develop sudden/dramatic changes in blood counts or increasing blasts on the peripheral smear, we perform a bone marrow examination to assess disease progression. For modest changes in blood counts or symptoms, repeating a bone marrow examination is generally not necessary.

●Treatment – Patients should be encouraged to participate in clinical trials, when available. Treatment options for patients with refractory or recurrent disease are influenced by prior therapy, as described separately. (See "Treatment of lower-risk myelodysplastic syndromes (MDS)", section on 'Second-line and later treatment'.)

CLINICAL TRIALS — Often there is no better therapy to offer a patient than enrollment onto a well-designed, scientifically valid, peer-reviewed clinical trial. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the United States National Institutes of Health (www.clinicaltrials.gov). For interested patients, relatives, and physicians, the Aplastic Anemia and MDS International Foundation maintains a website (www.aamds.org), which contains additional information as well as a listing of clinical trials in this disorder [9].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Myelodysplastic syndromes".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Myelodysplastic syndromes (MDS) (The Basics)" and "Patient education: Autologous bone marrow transplant (The Basics)")

●Beyond the Basics topics (see "Patient education: Myelodysplastic syndromes (MDS) in adults (Beyond the Basics)" and "Patient education: Hematopoietic cell transplantation (bone marrow transplantation) (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Description – Myelodysplastic syndromes (MDS) are hematologic malignancies characterized by clonal hematopoiesis, one or more cytopenias (ie, anemia, neutropenia, and/or thrombocytopenia), abnormal cellular maturation, and predisposition to progress to acute myeloid leukemia (AML).

●Diagnosis and classification – Diagnosis and classification is based on World Health Organization (WHO) classification. (See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)".)

●Prognostic category – The revised international prognostic scoring system (IPSS-R) (table 1) (calculator 1) or the original IPSS (table 2) (calculator 2) use bone marrow blast percentage, cytopenias, and cytogenetic findings to classify prognosis (see "Prognosis of myelodysplastic neoplasms/syndromes (MDS) in adults", section on 'IPSS (Original IPSS)'):

•Lower-risk MDS:

-IPSS-R: ≤3 points

-IPSS: ≤1 point

•Higher-risk MDS:

-IPSS-R: ≥3.5 points

-IPSS: ≥1.5 points

●Medical fitness – Medical fitness is determined by clinical and laboratory evaluation, performance status (PS) (table 3), and comorbid conditions (table 4) as (see 'Fitness categories' above):

•Medically-fit

•Medically-unfit, but not frail

•Frail

●Goals of care – Goals of care are to lessen symptoms, improve quality of life, and prolong survival, while minimizing treatment-related toxicity. Some patients are candidates for intensive, potentially curative therapies. (See 'Goals of care' above.)

●Lower-risk MDS management – Management is guided by symptoms and cytopenias (algorithm 1) (see 'Lower-risk MDS' above):

•Asymptomatic – We offer monitoring rather than immediate treatment, to avoid treatment-related adverse events (AEs) and because early treatment does not improve long-term survival. (See 'Asymptomatic' above.)

•Symptomatic – Treatment is guided by severity of cytopenias and symptoms (eg, transfusion requirements, progressive cytopenias, a declining quality of life). Lower-intensity therapies (eg, epoetin alfa, growth factors, iron chelation, luspatercept, hypomethylating agents, immunosuppressive therapy, lenalidomide, or a targeted agent (eg, IDH inhibitor) have modest AEs, but are not curative. (See "Treatment of lower-risk myelodysplastic syndromes (MDS)", section on 'Symptomatic MDS'.)

Occasional patients with lower-risk MDS may choose intensive approaches that can alter the natural history, but they are associated with substantial morbidity and mortality. (See "Treatment of high or very high risk myelodysplastic syndromes", section on 'Intensive chemotherapy'.)

Some patients opt for supportive care alone, based on frailty or personal values. (See "Myelodysplastic syndromes/neoplasms (MDS): Management of hematologic complications in lower-risk MDS".)

●Higher-risk MDS management – Treatment is informed by medical fitness, pathologic features, and personal values. (See 'Higher-risk MDS' above.)

•Medically-fit – Treatment may include intensive or lower-intensity therapies, as guided by pathologic features (eg, TP53 mutation, adverse cytogenetics), targetable mutations (algorithm 2), suitability for transplantation, and personal preferences. (See "Treatment of high or very high risk myelodysplastic syndromes", section on 'Intensive chemotherapy'.)

•Medically-unfit, but not frail – We favor lower-intensity therapy, based on pathologic features, drug availability, and patient preference (algorithm 1). (See "Treatment of lower-risk myelodysplastic syndromes (MDS)", section on 'Lower intensity agents'.)

•Frail – Supportive care alone. (See "Myelodysplastic syndromes/neoplasms (MDS): Management of hematologic complications in lower-risk MDS".)

●Recurrent or refractory disease – Treatment for relapsed or refractory MDS is based on prior therapy. (See "Treatment of lower-risk myelodysplastic syndromes (MDS)", section on 'Second-line and later treatment'.)

ACKNOWLEDGMENTS

The UpToDate editorial staff acknowledges Elihu H Estey, MD, who contributed as an author for this topic review.

The editors of UpToDate acknowledge the contributions of Stanley L Schrier, MD as author on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Hematology, and his dedicated and longstanding involvement with the UpToDate program.