ESA Failure in Low-Risk MDS: ESA Failure Criteria and Emerging Options to Promote Transfusion Independence

Myelodysplastic syndromes (MDS) are a group of heterogenous clonal stem cell diseases characterized by bone marrow failure and their tendency to progress to acute myeloid leukemia (AML). The spectrum of the disease varies from indolent lower-risk disease to a higher risk of AML transformation and life-threatening disease. The treatment approach is traditionally tailored based on disease risk. For lower-risk MDS (LR-MDS), treatment goals are alleviating cytopenias and improving quality of life. For higher-risk MDS (HR-MDS), allogeneic stem cell transplant is considered early in the disease course, and hypomethylating agents (HMAs) are the standard of care.[1]

What is the best approach for disease risk stratification?
Once the diagnosis is established, risk stratification of MDS is the most crucial step. The Revised International Prognostic Scoring System (R-IPSS) is the most used risk stratification system in MDS. 

It uses cytogenetics, cytopenias, and bone marrow blasts to determine which risk category a patient is in. These categories are predictive of survival and AML transformation.[2] Bernard and colleagues sought to incorporate molecular mutations into a new MDS risk stratification, IPSS-Molecular (IPSS-M). This study included 2,957 patients and retained clinical variables from R-IPSS while incorporating genetic alterations. IPSS-M categories resulted in re-stratification of 46% of patients. Of these, 74% were upstaged and 26% were downstaged. Currently, risk assessment of MDS should include both clinical and molecular variables.[3]

What is the natural history and current treatment landscape of LR-MDS?
The major morbidity and mortality in LR-MDS is related to cytopenias and their complications as well as the interplay of the cytopenias with other comorbidities. Unfortunately, a large subset of LR-MDS patients do not receive active therapy.

In a recent study of 1,914 LR-MDS patients at our center, 32% progressed to HR-MDS and/or AML. Progression to HR-MDS and/or AML was significantly associated with risk factors such as thrombocytopenia, neutropenia, elevated ferritin, elevated bone marrow blasts, hypoalbuminemia, and somatic mutations such as SRSF2, NRAS, ASXL1, TP53, RUNX1, and IDH1/2. Interestingly, of those patients with LR-MDS who did not progress to HR-MDS or AML, one-third had an estimated overall survival of <2 years, and half of those deaths were MDS related [4].

We aimed to identify clinical characteristics, treatment patterns, and outcomes of patients with LR-MDS by using the Connect® Myeloid Disease Registry (NCT01688011). Patients were stratified into groups by severity of anemia: no/mild anemia (> 10 g/dL), moderate anemia (8-10 g/dL), and severe anemia (< 8 g/dL). Patients with moderate or severe anemia accounted for 63.5% of the LR-MDS patients. More than half of the patients (62.1%) received no treatment or supportive care, including 37.0% with moderate anemia and 13.6% with severe anemia. Erythroid-stimulating agents (ESAs) and HMAs were the most common treatments used. Patients with moderate or severe anemia had significantly worse overall survival than patients with no/mild anemia (30 months, 26 months, and 63 months, respectively; P < 0.0001). While most patients did not progress beyond LR-MDS, the mortality of half of all patients was directly related to their disease.[5]

What are the goals of therapy, and how is response assessed?
In LR-MDS, most patients are anemic and become transfusion dependent, requiring the initiation of therapy. The goal of therapy in LR-MDS is to alleviate cytopenia and improve overall quality of life. Patients rarely require treatment for isolated neutropenia or thrombocytopenia, but co-occurrence of cytopenia may dictate the choice of therapy.

The International Working Group (IWG) 2006 response criteria for MDS has largely been used as a standardization of clinically meaningful treatment responses in MDS and has been adopted in clinical trials but not routinely followed in practice. Red blood cell transfusion independence (RBC-TI) had been the primary endpoint for drug approval for treating anemia in LR-MDS.[6] In 2018, the IWG proposed modifications for hematologic improvement criteria in an attempt to improve response criteria.

An erythroid response should include RBC-TI among patients with baseline transfusion dependency or a meaningful reduction in RBC transfusions, translating to improve quality of life. In patients with a low RBC transfusion burden, an objective hemoglobin (Hgb) increase associated with improved quality of life is also considered meaningful. Durability of response is an important factor.[7]

There is no clear guidance on when to initiate therapy, but in general, symptomatic anemia or red blood cell transfusion dependence (RBC-TD) is considered an indication to start treatment. On the other hand, treatment failure is not clearly defined, especially in real-world practice. It should be considered primary failure if patients do not achieve RBC-TI or a meaningful reduction after 8-12 weeks of treatment or an objective Hgb increase with improved symptoms in non-RBC-TD patients. Secondary treatment failure is defined as loss of an initial response either by the need for further RBC transfusions or a significant worsening of symptomatic anemia. Unfortunately, many patients continue treatments with no clear evidence of benefit and are unable to achieve stable blood counts or decrease their transfusion needs.

Which treatment option for anemia and for whom?
Erythroid-stimulating agents
The use of ESAs in LR-MDS yields responses in up to 40% of patients receiving doses equivalent to 40,000-60,000 units of epoetin alpha weekly; the median duration of response is 12-24 months. A model was developed and validated to identify patients who were likely to respond to ESAs. The model is based on pretreatment endogenous serum erythropoietin (EPO) concentration (<100, 100-500, or >500 U per liter) and RBC transfusion burden (< or ≥2 U per month). This model can determine whether a patient has a high (74%), intermediate (23%), or low (7%) probability of erythroid response.[8]

Lenalidomide
In patients with transfusion-dependent MDS with del5(q), lenalidomide (LEN) is the treatment of choice. The phase 2 MDS-003 trial included patients with MDS with 5q31 deletion who were considered to be low to intermediate-1 risk by the International Prognostic Scoring System (IPSS). The study demonstrated a 76% overall response rate, and 67% achieved transfusion independence, with a median time to response of 4.6 weeks and duration of response that exceeded 2 years.[9] The MDS-004 phase 3 trial compared LEN 10 mg daily for 21 days every 28-day cycle versus continuous treatment with LEN 5 mg daily versus placebo. Both the 10-mg and 5-mg dose showed higher responses than placebo with transfusion independence in 53.6%, 33.3%, and 6% of patients, respectively (P < 0.001).[10] In the Sintra-Rev phase 3 randomized control trial, LEN 5 mg daily was compared to placebo in non-transfusion-dependent patients with LR-MDS who were low and intermediate-1 risk by IPSS with isolated del(5q). Results demonstrated that, compared to placebo, a low dose of lenalidomide (5 mg daily) prolonged time to transfusion dependency (75.7 months vs 25.9 months in placebo).[11] Those findings suggest that time to transfusion dependency with active therapies may become a reasonable endpoint and goal of therapy.

Lenalidomide was also investigated in patients with lower-risk non-del5(q) MDS. The use of LEN monotherapy provided transfusion independence rates of 20%-30% in patients who were ESA refractory.[12] Further, LEN was used in combination with ESAs in those who had a suboptimal response to LEN monotherapy and were refractory to ESAs. A randomized clinical trial revealed combination therapy had an erythroid response of 28.3%, compared to 11.5% with LEN alone, with durable responses and a median duration of 23.8 months versus 13 months.[13]

Luspatercept
Luspatercept is a human-derived activin receptor II ligand fusion trap protein which has been shown to neutralize the TGF-beta superfamily and inhibit SMAD proteins to allow for effective erythropoiesis in preclinical studies. It is the first in a class of erythroid maturation agents releasing terminal erythroid differentiation block by TGF-B ligands. The PACE-MDS trial enrolled patients with low- or intermediate-1-risk MDS with anemia with or without a need for RBC transfusion. Higher responses were observed among patients with ringed sideroblasts (69% and 42%), SF3B1 somatic mutation (77% and 44%), and serum EPO <200 IU/L (76% and 53%).[14] These findings were validated in the phase 3 Medalist trial. RBC-TD patients with low- to intermediate-risk MDS-RS who were refractory or unlikely to respond to ESAs were randomized to receive placebo or luspatercept. Results showed 38% of those who received luspatercept were transfusion independent for 8 weeks or longer, as compared with 13% of those in the placebo group. Those who had low transfusion requirements were also found to have higher responses. Luspatercept was relatively well tolerated and infrequently required discontinuation; the most common side effects were fatigue, gastrointestinal symptoms, peripheral edema, and asthenia. Most patients required the higher dose of luspatercept to achieve a response.[15]

Luspatercept is FDA-approved for patients with RBC-TD anemia due to MDS with ringed sideroblasts and currently considered the treatment of choice after ESA failure or in patients with a low chance of ESA response. An ongoing clinical trial (NCT03682536) is evaluating the use of ESA versus luspatercept in the up-front setting to ESA-naïve low-risk MDS patients.

Hypomethylating agents
Hypomethylating agents (HMA) are the standard of care for HR-MDS but are also used for LR-MDS patients in the US. A 5-day HMA regimen is most commonly used in LR-MDS, with response rates of 40% reported.[16] Promising data were also presented with a 3-day regimen of HMA in LR-MDS.[17]

Oral HMAs are also being evaluated for use in MDS. Oral decitabine (C-DEC) is approved for intermediate- and higher-risk MDS by IPSS-R, and studies demonstrated an almost 100% bioavailability equivalence to intravenous decitabine. Oral azacytidine (CC-486) is currently being tested in LR-MDS.[18]

HMAs should seldom be used as first-line therapy in low-risk MDS since anemia is usually the most common cytopenia in MDS. Other options such as lenalidomide, ESAs, and luspatercept offer hematologic improvement and usually have a better side effect profile and higher responses if used prior to HMA.

How do I treat anemia in lower-risk MDS?

In our practice, only patients with lower-risk MDS who require RBC transfusions or have symptomatic anemia (typically Hgb < 9.0 g/dL) are considered for treatment of their anemia. If patients are not RBC-TD and endogenous serum EPO is <500, ESAs are our first option of therapy. We begin with an 8-week trial and continue treatment among responders or consider shifting treatment if there is no clear response.

After ESA primary or secondary failure, lenalidomide is our treatment of choice if patients have del5q. If patients have ringed sideroblasts, luspatercept is our treatment of choice. In non-del5q patients without ringed sideroblasts who only have isolated anemia, we may consider a lenalidomide and ESA combination. In a very small subset of patients who are young or have hypoplastic MDS, we may consider immunosuppressive therapy. We reserve the use of HMA as a last resort for treating anemia or if concomitant cytopenias need treatment. Finally, we may consider allogeneic stem cell transplant in younger patients after the failure of the above-mentioned options.

Managing MDS requires an experienced hematopathologist along with a specialized hematologist. The goals of therapy should be individualized based on shared decision-making between patients and physicians where the patient is informed about the disease and its risks, as well as the benefits and possible adverse events of treatment. Treatment is tailored based on patients’ goals, addressing patient quality of life and risk of disease. Tools for objectively assessing the quality of life specifically for patients with MDS have been developed and validated.[19] Those tools should be integrated into both clinical trials and daily practice.

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