MDS in the Lower-risk Patient: The Current Treatment Algorithm

Dr. Hetty E. Carraway
Hetty E. Carraway, MD, MBA, FACP
Associate Professor of Medicine
Vice Chair, Strategy and Enterprise Development
Hematologic Oncology and Blood Disorders
Taussig Cancer Institute, Cleveland Clinic
Cleveland, Ohio

How is low-risk MDS identified and treated today in your practice? Read a recent interview with Dr. Hetty Carraway where she discusses lower-risk myelodysplastic syndromes (MDS) defined by the International Prognostic Scoring System (IPSS) and an updated “revised” version (IPSS-R). In this discussion, Dr. Carraway provides readers with an overview of current standards of care and where the newly approved agent luspatercept fits in the treatment paradigm.

Could you please provide a brief definition of what constitutes lower-risk vs higher-risk disease in patients with myelodysplastic syndromes (MDS), and how lower-risk disease is assessed.

While some patients with MDS are incidentally discovered when a blood count is performed for another reason, most patients diagnosed with MDS come to medical attention because they are symptomatic. They may present either to a physician or other practitioner complaining of new onset of fatigue, decreased stamina, shortness of breath with exertion, recurrent minor bleeding, or easy bruising.1 Upon evaluation, most patients have anemia, and some have thrombocytopenia, neutropenia, or a combination of those three. These blood counts at diagnosis can be quite variable and heterogenous. 2,3

The way that we differentiate lower-risk MDS from higher-risk MDS is by using the parameters in the International Prognostic Scoring System (IPSS) that were established by Greenberg, et al., in the late 1990s, and updated in the “revised” version, the IPSS-R, published in 2012. Parameters in the IPSS-R include cytogenetic risk (ie, chromosome status), marrow blast percentage, and the number of cell lines affected along with the severity of low blood counts (eg, cytopenias).3,4 The IPSS-R score is tabulated and patients are then assigned to one of five risk groups: very low-, low-, intermediate-, high-, or very high-risk categories. Patients that fall into the very low- or low-risk categories are classified as having lower-risk MDS while those who fall into the high/very high designation are considered to have higher-risk MDS. The intermediate-risk group of patients fall in between the lower- and higher-risk classifications. These patients are a more heterogeneous group, and some behave indolently while others progress more rapidly than expected.2,3 The original IPSS included four risk groups rather than the five in the IPSS-R: low, intermediate-1, intermediate-2, and high risk, with the first two being “lower” risk and the other two “higher” risk.4

Patients with severe cytopenias may have minimal symptoms while those with milder cytopenias may have very bothersome symptoms.1,2 As an example from my clinical practice, some of the more physically active patients will come in and complain that they previously ran five miles regularly, but now it is taking them longer to achieve that same distance, or they are needing to stop and rest during their typical run. They have identified a significant change from the baseline level of exercise that has altered their quality of life.

How would you define goals of therapy for patients with lower-risk MDS, and how are erythropoiesis-stimulating agents (ESAs) used in the lower-risk patient population with anemia?

The goals of therapy in the lower-risk MDS patient population are primarily to reduce and manage their symptoms. While it would be helpful to delay progression to higher-risk disease, no therapies are currently available that have demonstrated this impact. If a patient is asymptomatic, they can be followed with watchful waiting, supporting them with checking labs and clinical check-up visits as long as they remain asymptomatic.2 For a patient who is symptomatic, therapy with supportive agents such as ESAs may be initiated. To do this, a patient’s erythropoietin (EPO) level in the blood must be checked. MDS patients with a serum EPO <100 U/L have a greater than 70% chance of responding to ESA-based therapy, especially if they have a low need for packed red blood cell (PRBC) transfusion. For those patients with a serum EPO level that is >500 U/L, giving them an exogenous supply of erythropoietin with an ESA is much less helpful, with a <10% likelihood of response to ESA therapy, especially if they are requiring frequent PRBC transfusion support.2,5

Some lower-risk patients with anemia may also have chromosomal aberrations that can help direct therapy. Patients with an isolated deletion of chromosome 5q [del(5q)] who become transfusion-dependent may respond to the oral immunomodulatory agent lenalidomide, and this treatment may result in transfusion independence with good and often durable therapeutic response. Data have demonstrated that patients treated with lenalidomide have a 65% to 75% rate of transfusion independence and 30% to 40% cytogenetic remission in these patients.2,6,7 Patients with other genetic abnormalities in addition to del5q may not respond well to this agent. For example, patients with MDS and isolated del(5q) and a TP53 mutation have been found to have a poorer response to lenalidomide and a higher risk of transformation to acute myeloid leukemia (AML).8,9

The benefit of lenalidomide in patients without del(5q) has been investigated, and the response rate is lower, with only a 27% response rate seen with regard to transfusion independence, and the improvement is not as durable as with del(5q).10 In addition, there are data from the E2905 Intergroup phase 3 study in which patients who had not responded to an ESA or were ineligible for ESA because of high blood EPO level received oral lenalidomide 10 mg daily for 21 days as a single agent vs lenalidomide (same dose and schedule) plus an ESA, epoetin alfa at a dose of 60,000 units once a week. Results demonstrated that patients who received lenalidomide plus ESA had a higher major erythroid response after 12 and 16 weeks of therapy, and the duration of their major erythroid response was longer vs lenalidomide alone. It may be reasonable to consider this combination therapy for low-risk non-del(5q) MDS patients in that setting.11 One study by Santini, et al., assessed health-related quality of life (HRQoL) in patients with lower-risk non-del(5q) MDS treated with lenalidomide and found that this agent was associated with benefit vs placebo across five QoL-related areas, namely fatigue, dyspnea, global HRQoL, and physical and emotional functioning.12 For my MDS patients who are transfusion dependent with del(5q), I typically start them on lenalidomide and follow them for a couple months to see if there will be a response.

Part of the work-up for any of our MDS patients is a next-generation sequencing (NGS) mutation panel, and this mutation panel includes evaluation for the mutational status of the TP53 gene, which is a high-risk mutation. Patients who have a TP53 mutation will have a decreased likelihood of response to lenalidomide. Even if there is a clinical response (eg, transfusion independence), the duration of response is often shorter compared to those without mutated TP53. In such cases we often refer patients with del(5q) and mutated TP53 for a bone marrow transplant consultation if they are age-appropriate and have manageable comorbidities, but they tend to do less well with transplant also. I think it is reasonable to recommend transplant evaluation for patients with TP53-mutated or other “higher-risk genetics” even though they may be a lower-risk patient by IPSS or IPSS-R. This is important, because otherwise we refer to transplant only when they become a higher-risk MDS patient.

How should patients with lower-risk MDS and cytopenias beyond anemia be managed?

In the evaluation of patients with cytopenias other than anemia, a full evaluation would include looking for evidence of: (1) medications that could be causing the low blood count; (2) infections including human immunodeficiency virus (HIV), hepatitis B, hepatitis C or others; (3) rheumatological conditions such as rheumatoid arthritis or lupus; (4) thyroid disorders; (5) nutritional deficiencies including copper and zinc levels; and (6) liver and renal dysfunction.13 If this evaluation is unrevealing, and bone marrow biopsy is also unrevealing, molecular genetic testing can be helpful.

In some cases it might be important to consider evaluation for a congenital abnormality such as ANKRD26 or RUNX1, where there is a germline (inborn) mutation that predisposes to a platelet disorder. Patients with ANKRD26 or RUNX1 mutations also have an associated increase in MDS and AML. These patients have a lifelong mild-to-moderate thrombocytopenia but have a mild bleeding phenotype and do not have any severe issues with bleeding.14,15

As previously mentioned, the more common reasons for low platelet levels include exposure to antibiotics and other medications, and this potential culprit must always be ruled out.16

For patients who are asymptomatic with stable but low platelet counts, monitoring without therapy can be appropriate. There are therapies called thrombopoiesis stimulating agents that are similar to ESAs and boost platelet counts; however, a study of one of these trichostatin A’s (TSAs), romiplostim, in lower-risk MDS was discontinued because of a slight increase in blasts in MDS patients receiving that agent, with 12% who received the drug progressing to AML vs 11% who received placebo. A five-year follow-up showed that there was no difference in clinical outcomes for MDS patients that were treated with romiplostim vs placebo. Overall, you really can just be fixing a number in regard to platelets but not altering disease biology, since in some patients the platelet number goes up but there is no change in bleeding events.17 Bleeding risk from other factors besides platelet number must be addressed, and I recommend that MDS patients with severe thrombocytopenia due to MDS avoid aspirin, nonsteroidal anti-inflammatory agents and fish oils.

Patients with mild neutropenia can often also be monitored, but those with more severe neutropenia are at risk of infection, which is the leading cause of death in MDS. Neutropenia in patients with lower-risk MDS may appear to respond to myeloid growth factors (G-CSF/filgrastim or tbo-filgrastim or PEG-filgrastim, or GM-CSF/sargramostim) but these drugs have not been shown to improve survival and have minimal effect on decreasing infection risk, so they are not widely used.2,18 As previously noted, I also make sure to evaluate for other causes of secondary immunocompromise such as rheumatoid arthritis or lupus.

The use of immunosuppressive therapy such as antithymocyte globulin (ATG), corticosteroids, or cyclosporin can be considered in these patients if therapy is warranted, but selection of treatments in these cases is difficult. In some series, low bone marrow cellularity has been associated with a higher likelihood of response to immunosuppressive therapy.2,19,20

What is the potential role of TGF-beta (TGF-β) pathway inhibitors in patients with lower-risk MDS?

Luspatercept is an investigational first-in-class erythroid maturation agent that neutralizes the TGF-β superfamily ligands and subsequently inhibits aberrant SMAD2 and SMAD3 signaling by way of that inhibition. By inhibiting those suppressors, it enhances late-stage erythropoiesis in MDS. Data from the phase 2 PACE-MDS study evaluated luspatercept in lower-risk patients with MDS who were ESA-naïve as well as those who had previously received ESAs and lost their response or never responded. In the PACE-MDS study, patients with SF3B1 mutation and/or ring sideroblasts had a very high likelihood of hematologic improvement with luspatercept treatment: 76% if the serum EPO level was <500 U/L, and 67% if the serum EPO level was >500 U/L. For those MDS patients that did not have this SF3B1 mutation or ring sideroblasts, the likelihood of hematologic response was lower: 38% if EPO was <500 and only 8% if EPO was >500.21

The results of this PACE study prompted the start of the randomized, placebo-controlled MEDALIST trial, the results of which were first reported in December 2018. The MEDALIST trial included patients with very low-, low-, and intermediate-risk MDS who had either SF3B1 mutations, ring sideroblasts, or both, and had lost clinical response to ESA-based therapy or never responded or had an EPO level >200 U/L and were unlikely to respond to an ESA. Updated data presented at the 2019 American Society of Hematology (ASH) Annual Meeting on the results from the MEDALIST trial reported that 47.1% of patients treated with luspatercept achieved that transfusion independence (defined as no administration of PRBCs in 56 days) versus 15.8% of patients on placebo.22 The results of this trial were published in the New England Journal of Medicine in January 2020; among 229 patients, transfusion independence was reportedly achieved in 38% of patients who received luspatercept vs 13% who received placebo.23 Based upon this data, luspatercept was approved by the United States Food and Drug Administration (FDA) for the treatment of anemia in adult patients with very low- to intermediate-risk MDS with ring sideroblasts and patients with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis after they have progressed on ESA therapy and who require infusion of ≥2 PRBC units over 8 weeks.24

Naturally, there is also interest in evaluating whether or not luspatercept can decrease transfusion dependence in all MDS patients irrespective of whether or not they have SF3B1 mutation or ring sideroblasts. The COMMANDS Study is an ongoing investigation of luspatercept vs ESA-based therapy in transfusion-dependent very low-, low- and intermediate-MDS in the upfront setting.25

Other than lenalidomide, what other agents would you consider for patients with lower-risk MDS who are refractory to ESAs?

One agent currently undergoing investigation is roxadustat. This drug is a first-in-class hypoxia inducible factor (HIF) inhibitor, and it is thought to promote erythropoiesis by increasing endogenous erythropoietin signaling, improving iron regulation, and reducing hepcidin. Currently, this agent is being studied in an ongoing phase 3 study at a number of sites, focusing on very low to intermediate primary MDS and patients with less than 5% blasts who also have a low transfusion burden. The goal here is to see if the need for transfusions can be reduced using this oral medication. A 2.5 mg/kg starting dosage will be used for the ongoing portion of trial, with preliminary results showing that half of patients studied (12 of 24 total) who received ≥2.5 mg of roxadustat achieved a ≥50% reduction in the need for RBC transfusion in any 8-week period compared to baseline. Enrollment in this clinical trial has been challenging given the narrow eligibility criteria, so it may be some time before we have any further data about this agent in MDS.26

In addition to these agents, data presented at the most recent ASH Congress in 2019 focused on a novel drug called APR-246. APR-246 is a prodrug spontaneously converted to methylene quinuclidinone that binds to cysteines in mutant p53 protein encoded by the TP53 gene, changing the inactive p53 to a reactivated state, restoring its pro-apoptotic and cell cycle arrest functions. While it lacks strong activity as monotherapy, it has been studied in combination with azacitidine in patients with p53-mutated MDS and AML. In these data, APR-246 has shown an overall response rate (ORR) of approximately 75% in the evaluable population per protocol, with a 63% response rate in the intent-to-treat (ITT) population.27 Another study of p53-mutated MDS and AML found that this combination produced complete response (CR) in 61% of patients with MDS, with 41% of patients with either MDS or AML achieving complete or partial cytogenetic response.28 In January 2020, the FDA granted a breakthrough designation to this drug combination for the treatment of p53-mutated MDS. This agent had previously received the FDA’s fast-track and orphan drug designation in April 2019, and phase 3 investigation of azacitidine monotherapy vs azacitidine plus APR-246 is ongoing.29

There are other compounds of interest such as magrolimab, an anti-CD47 antibody and imetelstat, a telomerase inhibitor, among others.25

Finally, is there a place for use of hypomethylating agents (HMAs) in lower-risk MDS?

These agents are used primarily in higher-risk disease, and in a manner that can be quite cytotoxic. There are data from a study where the agent was used in a reduced schedule (3 days per month of decitabine or 5 days per month of azacitidine) in lower-risk MDS and MDS/myeloproliferative neoplasm overlap syndromes. The ORR in this study was 70% for the HMA decitabine and 49% with azacitidine with rates of transfusion independence being 32% vs 16%, respectively.2,30 Overall, it is still not clear how much lower doses of HMAs will benefit patients with lower-risk MDS.


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