Can you provide an overview of how anemia impacts patients who are diagnosed with MDS?

Published research has shown that the majority of people with myelodysplastic syndromes (MDS) are anemic when they are initially diagnosed or will develop symptomatic anemia over time. Anemia is characterized by persistently low hematocrit or hemoglobin levels. In general, MDS patients who are anemic tend to experience fatigue and decreased exercise tolerance, but the severity varies. Those with moderate anemia often present with some fatigue that may be accompanied by heart palpitations, shortness of breath, and pale skin. In severe cases, patients may be pale and report having chronic fatigue and/or shortness of breath that is overwhelming. Because severe anemia reduces blood flow to the heart, older patients may be at higher risk of having cardiovascular symptoms. Although symptomatic chronic anemia is seldom life threatening, it can drastically reduce quality of life.1,2

The overarching goals of therapy in MDS are to minimize symptoms, improve blood counts, decrease transfusions and infections, and prolong stable disease. The hope is that meeting these goals will prolong survival outcomes and improve quality of life.2 When managing MDS, the goals of therapy must be individualized for each patient depending on their level of risk, which is commonly determined using the Revised International Prognostic Scoring System (IPSS-R). Managing anemia and reducing transfusion dependency are the primary strategies for managing low-risk MDS patients. Improving erythropoiesis and eliminating fatigue and symptoms are the main therapeutic goals for low-risk MDS patients.3 These goals are different than the ones for high-risk disease, where the chief concern is reducing risks for progression to more severe forms of leukemia – acute myeloid leukemia (AML).

What treatment options are available to manage persistent anemia in patients with low-risk MDS, and what factors should be considered when deciding on therapy?

Several therapies are available to manage persistent anemia in low-risk MDS; key factors directing on the choice of treatments include the serum erythropoietin (EPO) level and the presence or absence of ring sideroblasts. Symptomatic patients with low serum EPO levels (<200 IU/L) and no ring sideroblasts are likely to respond to treatment with erythropoietic stimulating agents (ESAs), such as recombinant erythropoietin or darbepoetin. In the community setting, many low-risk MDS patients are under-dosed when they are given ESAs. Some of these individuals could achieve a response by increasing the ESA dosage, and/or adding granulocyte colony-stimulating factor (G-CSF) as an ESA adjuvant. When ring sideroblasts are present, MDS patients will not respond to erythropoietin alone but may respond to erythropoietin plus G-CSF. Such patients may respond to high dose darbepoetin; it is not clear that G-CSF synergizes with the latter ESA.

Beyond EPO levels and ring sideroblasts, the presence or absence of deletion of the long arm of chromosome 5 [del(5q)] helps direct therapy for anemia in low-risk MDS patients. Del(5q) can be detected in approximately 10% of patients with low-risk MDS. Lenalidomide frequently induces transfusion independence in low-risk MDS patients with del(5q).4 Some authorities recommend a therapeutic trial of ESA in such patients if the EPO level is <200 before initiating lenalidomide; however, many patients in the group have higher concentrations of serum EPO. For transfusion-dependent low-risk MDS patients without del(5q), there are few effective treatments following ESA failure; lenalidomide can induce transfusion independence in approximately 25%. Immunosuppressive therapy, such as antithymocyte globulin with cyclosporine, should be restricted to select patients.4,5

The DNA methyltransferase inhibitors (DNMTi) azacitidine and decitabine can induce transfusion independence in a significant proportion of patients. Although these DNMTi have been shown to improve survival or delay disease progression in patients with higher-risk MDS, potentially negative impact disease stability in lower-risk disease has not been explored in depth. Current studies of oral formulations of azacitidine and decitabine may provide opportunities to study the impact of administration of these drugs on the genome of low-risk MDS.6

Can you describe the efficacy and safety data that have been seen with emerging agents as treatment for anemia in patients with low-risk MDS?

Luspatercept, a first in class erythroid maturation injectable agent which binds to select TGFβ superfamily ligands, has shown significant activity in symptomatic anemia in lower-risk MDS. Treatment with this agent reduced Smad2/3 activation, anemia, erythroid hyperplasia, and ineffective erythropoiesis in a mouse model of MDS.7 A phase 2 trial demonstrated that the drug was well tolerated and effective for the treatment of anemia in lower-risk MDS, with a particularly strong signal in patients with ring sideroblasts.8

The phase 3 MEDALIST trial evaluated the efficacy and safety of luspatercept in red blood cell transfusion-dependent, IPSS-R-defined very low-, low-, or intermediate-risk non-del(5q) MDS patients with ring sideroblasts. Participants in this trial were refractory, intolerant, or unlikely to respond to ESAs based on their serum EPO level. They were randomized in a 2:1 ratio to receive either luspatercept or placebo every 3 weeks for 24 weeks or longer. According to data that will be presented at the 2018 American Society of Hematology (ASH) annual meeting, nearly 38% of patients receiving luspatercept achieved the primary endpoint of RBC-transfusion independence for 8 weeks or longer, compared with a 13% rate seen for the placebo group. Luspatercept was also generally well tolerated.9 The drug is likely to be approved by the FDA in the near future, and clinical trials are planned to compare luspatercept with an ESA in low-risk MDS patients with and without ring sideroblasts.10

Another investigational drug for treating anemia in low-risk MDS in those who relapse or are refractory to ESAs is imetelstat, a first-in-class telomerase inhibitor that targets cells with short telomere lengths and active telomerase. At the 2018 European Hematology Association annual meeting, data were presented from IMerge, an ongoing global phase 2/3 study investigating imetelstat in RBC transfusion-dependent patients with low-risk MDS. Higher response rates were seen in patients who were lenalidomide and hypomethylating agent (HMA) naïve without del(5q).11 Updated data from IMerge will be presented at the 2018 ASH annual meeting. Currently, data show that 37% of low-risk MDS patients who received single-agent imetelstat became transfusion independent, with a median duration of 10 months and limited side effects.12

With new insights into the biology of MDS from next-generation sequencing (NGS), new therapies will be developed to reduce the burden of red blood cell (RBC) transfusions after ESA failure and approaches to therapy will be more individualized. NGS has significantly contributed to the diagnosis and prognostication of MDS.13

What recommendations do you have for community oncologists regarding patient and caregiver education when managing anemia in low-risk MDS patients?

When managing anemia in MDS, it is important to ensure that patients and their caregivers have realistic expectations about their treatment. They should understand that the fatigue they are experiencing as a result of their anemia can be ameliorated to the point where quality of life will significantly improve. Patients should understand that alternative therapies may be helpful if their hematocrit and hemoglobin levels do not improve; ongoing fatigue should not be the expectation.

Patients with low-risk MDS should also be informed that different trials of therapy may be required to manage anemia, and the duration of these trials varies from drug to drug. For example, it will take about 12 weeks to determine whether ESAs are likely to be effective, but it could take longer to determine whether patients will respond to DNMTi. Educating patients on why they need these drugs is also paramount to ensure there is “buy in” and an understanding of how certain therapies will improve how they feel. The education should begin with a discussion on goals of care and ensuring patients understand the need for close monitoring of responses to treatment. Referrals to MDS specialists are also recommended in national guidelines, especially for hard-to-treat cases.1

What key takeaway messages should community oncologists keep in mind when managing anemia in patients with low-risk MDS?

The National Comprehensive Cancer Network guidelines recommend that every patient who is diagnosed with low-risk MDS have their bone marrow closely examined, an iron stain performed, and cytogenetics reviewed. Serum EPO levels should be analyzed early in the disease course so that therapy can be tailored appropriately.2 Recent studies suggest it is increasingly important to perform NGS in low-risk MDS patients to learn more about the mutations that are present. ESAs, DNMTi, and lenalidomide are viable treatment options for many patients, but these therapies may not be effective for everyone with low-risk disease. Several investigational agents—luspatercept, in particular—are far along in clinical development and are likely to be approved in the near future. These therapies will offer an alternative treatment option for patients with specific genetic abnormalities.