Disease Overview

Myelodysplastic Syndromes (MDS) are a group of uncommon blood disorders where the bone marrow does not produce enough healthy blood cells. This leads to low levels of red blood cells, white blood cells, and platelets. MDS can vary widely in severity, and in some cases, it can progress to a more serious condition called acute myeloid leukemia (AML). Typically affecting older adults, with most diagnoses occurring around age 70, MDS shows a higher prevalence in men than women and becomes more common with advancing age. In the United States, an estimated 4.9 out of every 100,000 individuals are diagnosed with MDS annually.

Classification

The development of MDS involves a complex interplay of genetic and epigenetic abnormalities, alongside disruptions in the bone marrow environment. Somatic mutations, including TP53, SF3B1, and TET2, play pivotal roles in impairing blood cell production and causing accumulation of immature and dysfunctional cells. Chromosomal abnormalities, such as deletion of chromosome 5q, further contribute to MDS pathogenesis. MDS can manifest as either a primary condition or secondary to treatments like chemotherapy, with symptoms typically appearing 2 to 7 years post-exposure. 

Signs and Symptoms

Common signs and symptoms of MDS include fatigue, weakness, abnormal pale skin, and shortness of breath, stemming from decreased red blood cell count. Reduced platelet count may lead to increased bleeding or bruising, while diminished white blood cells elevate infection risk. 

Diagnosis and Prognosis

Diagnosing MDS involves a comprehensive evaluation, including a detailed medical history and physical examination. Laboratory tests such as complete blood count (CBC) and peripheral blood smear help identify causes of cytopenia. Bone marrow examination via aspiration and biopsy assesses morphologic dysplasia, blast cells, cellularity, and fibrosis. Further characterization may employ flow cytometry and molecular genetic testing, with conventional cytogenetic testing revealing non-random chromosomal abnormalities like del(20q), del(5q), +8, and −7/del(7q). Doctors use special scoring systems to classify and predict the prognosis of MDS. Two common systems are revised International Prognostic Scoring System (IPSS-R) and International Prognostic Scoring System -Molecular (IPSS-M). The revised International Prognostic Scoring System aids in predicting the patients’ risk (high, moderate, or low) in disease progression to AML based on bone marrow findings and blood cell counts. International Prognostic Scoring System -Molecular uses genetic testing to identify gene mutations for a more detailed risk assessment. 

Disease Management and Treatment

Every patient deserves to live comfortably and participate in daily activities with minimal symptoms. Treatment plans are tailored to each patient’s symptoms, disease features, and personal preferences. Effective management of low-, moderate-, or high-risk MDS involves prompt treatment to alleviate cytopenia, manage anemia, and improve quality of life. Individuals who display no symptoms are regularly monitored for any changes or progression of the disease. Patients who are symptomatic are eligible to receive supportive care and low-intensive therapy.  Supportive care is a treatment strategy that includes blood cell transfusions and antibiotic therapy to combat infections. Low-intensive therapy includes ESA, hypomethylating agents, Lenalidomide, Luspatercept, Imetelstat, IDH inhibitors,and immunosuppressant therapy. These treatments are used when there are ongoing transfusion needs, worsening blood counts, or declining quality of life. Multiple FDA-approved therapies target secondary conditions and MDS itself, offering a range of options for initial and subsequent treatment stages. The choice of treatment depends on the type and severity of the blood cell deficiencies, as well as the patient’s overall health and preferences. 

There are therapeutic options for patients with secondary conditions of anemia, thrombocytopenia, and multiple cytopenias. Anemia is a medical condition characterized by low red blood cell counts. If erythropoietin (EPO) levels are low (≤500 mU/mL), patients will be treated with erythropoiesis-stimulating agents (ESAs) or Luspatercept for three months.If EPO levels are high (>500 mU/mL), ESAs are unlikely to help, so other treatments are considered. Individuals with Thrombocytopenia (low platelets) can be treated with thrombopoietin receptor agonists (TPO-RAs). For cases with more than 10% blasts (immature blood cells), they may consider the use of hypomethylating agents or targeted therapies if TPO-RAs are ineffective. Patients with multiple cytopenias, a condition characterized by low levels of multiple blood cells, have treatment options that are specific to their disease features of personal preferences. 

First-line therapies include Reblozyl® (luspatercept), approved for anemia in low-risk MDS and MDS with ring sideroblasts/mutated SF3B1, and Revlimid® (lenalidomide), indicated for anemia in MDS with isolated del(5q). Reblozyl facilitates maturation of dysfunctional red blood cells, while Revlimid® inhibits abnormal cell proliferation. Second-line options like RYTELO™ (Imetelstat) target anemia in low- to intermediate-risk MDS by suppressing telomerase activity, necessitating vigilant monitoring for specific potential side effects.This therapy helps reduce the need for red blood cell transfusions in patients who do not respond to ESAs.

FDA-approved treatments for all MDS types encompass hypomethylating agents and immunotherapy agents. Immunotherapy like INQOVI® (decitabine and cedazuridine) is used for hypoplastic MDS, a type of MDS where the bone marrow is less cellular. Hypomethylating agents such as Vidaza® (azacitidine) and Dacogen® (decitabine) are used for other cases. Also, targeted therapy such as Ivosidenib and Enasidenib may be considered useful for patients who have inadequate response to first or second line agents. Ivosidenib is indicated for patients with MDS with IDG1 mutations. Enasidenib is indicated for patients with AML with IDH2 mutations. Although enasidenib is not approved for MDS, it can be used off-label for patients who need this therapy. Additionally, conventional chemotherapy including Cytosar-U®, Cerubidine®, and Idamycin® may be considered for high-risk MDS subtypes. Allogeneic stem cell transplantation, potentially curative, remains reserved for younger patients and those with high-risk disease. 

In conclusion, MDS is a complex group of disorders that require personalized care to manage symptoms and improve quality of life. Various treatment options are available, and the best approach depends on the specific characteristics of the disease and the patient’s preferences. Regular monitoring with CBCs every 3 to 6 months and periodic bone marrow examinations is essential for ongoing disease management and treatment assessment. Thus, tailored treatment strategies are key to managing MDS effectively.