The Latest in Managing Anemia for Patients With Myelodysplastic Syndrome (MDS)

Myelodysplastic syndromes (MDS) are a group of hematologic cancers characterized by the presence of one or more cytopenias, including anemia, neutropenia, and thrombocytopenia.

These conditions often lead to symptoms like fatigue, dyspnea, palpitations, and pallor. Effective management of anemia in MDS patients is crucial to alleviate symptoms and improve their quality of life.

Clinical evaluation

Health history

A thorough clinical evaluation is essential for managing MDS. During the history-taking process, it is important to ask the patient about symptoms related to anemia, such as fatigue, shortness of breath, palpitations, and pallor.

Additionally, inquire about symptoms related to thrombocytopenia and neutropenia. Document any prior blood transfusions or treatments for cytopenias, and evaluate comorbid conditions such as heart, lung, kidney, or liver dysfunction that might affect treatment options.

Other potential causes for cytopenias, including nutritional deficiencies, alcohol and drug use, medications, toxic exposures, autoimmune conditions, prior treatments with antineoplastic agents or radiotherapy, and risk factors for HIV infection, should also be assessed.

Physical examination

Physical examination of MDS patients may reveal pallor, tachycardia, tachypnea, dyspnea, mucosal ulceration, and signs of infections, bleeding, or bruising. Clinicians should also examine the liver, spleen, and lymph nodes.

Overview of management

MDS is a heterogeneous disease, and treatment must be individualized. Participation in clinical trials is encouraged when possible. The primary goals of care include alleviating MDS-related symptoms, improving quality of life, and prolonging survival. These goals should be established through discussions between the clinician, the patient, and, when appropriate, their relatives or loved ones.

Lower-risk MDS

Over 70% of patients with MDS, are classified as having lower-risk disease, and the majority of these patients will require blood transfusions as a component of their care to treat a common complication: anemia. Management of lower-risk MDS is guided by the presence and severity of symptoms and cytopenias.

Asymptomatic patients

For asymptomatic patients, monitoring rather than immediate treatment is often recommended to avoid treatment-related adverse effects.

Symptomatic patients

For symptomatic patients, management focuses on alleviating cytopenia-related symptoms and often includes transfusions. Symptomatic anemia in MDS is typically managed based on the severity of symptoms and the serum level of erythropoietin (EPO).

Management of symptomatic anemia

Anemia is the most common cytopenia in MDS, affecting more than three-quarters of patients. Symptoms related to anemia include fatigue, weakness, exercise intolerance, loss of appetite, weight loss, angina, dizziness, dyspnea, headache, cognitive impairment, and an altered sense of well-being.

For patients with hemoglobin (Hb) levels below 10 g/dL and associated symptoms, treatment options include:

• Erythropoiesis-Stimulating Agents (ESAs): These agents can stimulate red blood cell production and reduce transfusion requirements.
• Hypomethylating Agents (HMAs): Medications like azacitidine and decitabine can help alleviate symptoms and reduce the need for transfusions.
• Immunosuppressive Therapy: This approach can be beneficial for certain subtypes of MDS.
• Lenalidomide: This is particularly effective for patients with chromosome 5 deletion.
• Luspatercept: This is useful for reducing transfusion needs in specific cases.
• Targeted Agents: Various targeted therapies may also be considered based on clinical and laboratory findings.
  Higher-Risk MDS

Treatment of higher-risk MDS is informed by the patient’s medical fitness, pathologic features, and personal values.

Medically fit patients

For medically fit patients, individualized treatment may include intensive remission induction or lower-intensity treatments such as HMA- and/or venetoclax-based therapies. Eligibility for allogeneic hematopoietic cell transplantation should also be assessed.

Medically unfit but not frail patients

For patients who are medically unfit but not frail, lower-intensity therapy, such as HMA-based treatment with or without venetoclax and/or targeted agents, is preferred. The choice of treatment is guided by pathologic features, convenience, and patient preference.

Frail patients

Frail patients typically receive supportive care to manage symptoms and maintain quality of life.

The role of imetelstat in managing anemia

Imetelstat (brand name Rytelo) is a promising treatment option for reducing red blood cell (RBC) transfusion dependence in patients with lower-risk myelodysplastic syndromes (MDS) who either do not respond to erythropoiesis-stimulating agents (ESAs) or have lost their response to these agents. As a lipid-conjugated oligonucleotide, Imetelstat works by competitively inhibiting telomerase enzymatic activity.

“With the approval and availability of Rytelo [Imetelstat], we believe eligible patients with LR [low risk] MDS can potentially experience meaningful clinical benefit, particularly the potential for greater than 24 weeks of freedom from the burden of red blood cell transfusions and symptomatic anemia,” said Dr John A. Scarlett, chairman and chief executive officer of Geron, in a news release.

“The approval of Rytelo as the first telomerase inhibitor is a testament to the power of our science and the passion of our people to innovate in the field of blood cancer.”

Administration

Imetelstat is administered intravenously at a dose of 7.1 mg/kg over a two-hour infusion, repeated every four weeks. To mitigate infusion-related reactions, premedication is recommended. Monitoring includes obtaining a complete blood count (CBC) before initiating treatment, weekly during the first two cycles, and prior to each subsequent infusion. Dose adjustments, including reduction or delay, are necessary for patients experiencing thrombocytopenia or neutropenia.

In cases of infusion-related reactions, the treatment should be interrupted, and the infusion rate should be decreased. If severe reactions persist despite premedication and a reduced infusion rate, discontinuation of Imetelstat is advised.

Regulatory approval

Imetelstat is approved by the US FDA for use in adults with lower-risk MDS who are transfusion-dependent, defined as needing four or more units of RBCs over eight weeks and who have not responded to or lost their response to an ESA. Additionally, Imetelstat has received validation for marketing from the European Medicines Agency (EMA).

“For patients with LR-MDS and anemia who are transfusion dependent, we have very few options today and often cycle through available therapies, making the approval of Rytelo [Imetelstat] potentially practice-changing for us,” said Dr. Rami Komrokji, vice chair of the Malignant Hematology Department at Moffitt Cancer Center and an investigator of the pivotal IMerge clinical trial, in the news release.

“What is exciting about Rytelo [Imetelstat] is the totality of the clinical benefit across LR-MDS patients irrespective of ring sideroblast status or high transfusion burden, including sustained and durable transfusion independence and increases in hemoglobin levels, all within a well-characterized safety profile of generally manageable cytopenias.”

Imetelstat safety and side effects

Although reducing how often patients with MDS need to undergo blood transfusions is a major advancement, like all cancer therapies, there is the potential for side effects. This new study found that Rytelo has a manageable safety profile, with some side effects that can be controlled.

The most common serious side effects were:

• Neutropenia: 72% of patients
• Thrombocytopenia: 65% of patients

These side effects usually lasted less than two weeks and improved to milder levels in under four weeks for over 80% of patients. Other potential side effects included: Thrombocytopenia, increased liver enzymes (AST, ALT), fatigue, Joint/muscle pain, headache, sepsis, GI bleeding and hypertension.

What about luspatercept?

Luspatercept (brand name Reblozyl), an erythroid maturation agent, effectively treats anemia in MDS by enhancing late-stage erythropoiesis. It works by binding and “trapping” transforming growth factor (TGF) beta superfamily ligands, thus reducing aberrant Smad2/3 signaling. This mechanism is particularly beneficial in MDS with ring sideroblasts.

Approval and indications

Luspatercept has been approved by the US FDA for treating anemia associated with MDS with ring sideroblasts or mutated SF3B1. Additionally, the EMA has approved it for treating transfusion-dependent anemia in lower-risk MDS patients.

Clinical efficacy

Luspatercept has demonstrated superior efficacy compared to placebo in achieving transfusion independence (TI) in lower-risk MDS patients with ring sideroblasts. The phase 3 MEDALIST trial, which included 229 patients with either ≥15 percent ring sideroblasts or ≥5 percent ring sideroblasts if an SF3B1 mutation was present, showed promising results.

These patients, who had less than 5 percent bone marrow blasts and were refractory or unlikely to respond to ESAs, experienced significant benefits from luspatercept. The trial revealed that luspatercept achieved RBC TI for ≥8 weeks in 38 percent of patients compared to 13 percent in the placebo group, and TI for ≥12 weeks in 28 percent of patients versus 8 percent for placebo.

Luspatercept was generally well-tolerated, with most adverse effects being mild, including fatigue, diarrhea, asthenia, nausea, and dizziness. Long-term follow-up (median >26 months) indicated that the benefits of luspatercept continued to increase over time, with 45 percent of patients achieving ≥8-week TI compared to 16 percent in the placebo group, and 28 percent achieving ≥16-week TI versus 7 percent for placebo.

Moreover, luspatercept led to a ≥50 percent reduction in transfusion requirements in 50 percent of patients compared to 14 percent for placebo, and erythroid improvement in 59 percent of patients versus 17 percent per IWG 2006 criteria. The median duration of ≥8-week TI was 30 weeks for luspatercept and 17 weeks for placebo, with improvements observed in both high- and low-transfusion burden patients, and no new toxicity signals were reported.

Comparative efficacy

In a planned interim analysis of the phase 3 COMMANDS trial, luspatercept proved more effective than epoetin alfa in RBC transfusion-dependent, ESA-naive patients with lower-risk MDS. Interim results from 301 patients indicated that luspatercept achieved a higher rate of ≥12 weeks TI with a concurrent rise in mean hemoglobin of ≥1.5 g/dL (59 percent compared to 31 percent for epoetin alfa). The adverse effects were mostly mild and similar to those reported in previous studies.

In summary, luspatercept has shown significant promise in managing anemia in MDS, particularly in patients with ring sideroblasts, offering an effective treatment option with a favorable safety profile.