Expanding the Repertoire in Myelodysplastic Syndromes: Studying the Sequence of Therapies in Lower-risk Transfusion-dependent Disease

STUDY TITLE: A Study to Compare the Efficacy and Safety of Luspatercept (ACE-536) Versus Epoetin Alfa for the Treatment of Anemia Due to IPSS-R Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes (MDS) Participants Who Require Red Blood Cell Transfusions and Are ESA Naïve (COMMANDS)

CLINICALTRIALS.GOV IDENTIFIER: NCT03682536

PARTICIPATING CENTERS: Multiple worldwide

ACCRUAL: 347 participants

SPONSOR: Celgene and Acceleron Pharma Inc.

STUDY DESIGN: The COMMANDS trial is a randomized, phase III, open-label study comparing current standard-of-care therapy with epoetin alfa (EPO) to luspatercept (ACE-536) for the initial treatment of anemia in adult patients 18 years or older with lower-risk myelodysplastic syndrome (MDS) who require red blood cell (RBC) transfusions. Eligible patients have a confirmed diagnosis of MDS that is very low, low, or intermediate risk according to the Revised International Prognostic Scoring System (IPSS-R) and with fewer than 5% bone marrow blasts.¹  Participants must also have a serum erythropoietin level less than 500 U/L and require RBC transfusion support. Patients are randomized to receive standard treatment with EPO or experimental therapy with luspatercept.

The primary outcomes measure of this study is the proportion of patients who achieve RBC transfusion independence (RBC-TI) for 12 weeks, along with a mean hemoglobin increase of at least 1.5 g/dL, assessed between weeks 1 through 24 on study. Secondary endpoints include rates of RBC-TI lasting 24 weeks, hematologic improvement according to International Working Group (IWG) criteria,²  overall RBC transfusion burden, progression to acute myeloid leukemia (AML), and overall survival. Patient-reported outcomes, including quality of life, are also studied.

RATIONALE: Most patients newly diagnosed with MDS present with lower-risk disease (LR-MDS), defined by IPSS-R very low, low, or intermediate risk scores. Despite its benign-sounding name, most patients with LR-MDS suffer progressive anemia and related symptom burden. In general, patients with LR-MDS are monitored expectantly until they develop symptomatic anemia or RBC-TI, at which point therapies are initiated to improve symptoms and reduce or eliminate transfusion needs.³  For many years, only limited therapeutic options for these patients have existed. The most frequently used initial therapy has been and remains the use of erythropoietin-stimulating agents (ESAs), including epoetin alfa (EPO) and darbepoetin alfa, of which various formulations are available. ESA therapies have limited safety risks and show effectiveness in LR-MDS patients, with response rates between 45% and 73% in newly treated patients and durations of response lasting 10 to 19 months.⁴ 

For patients with MDS with isolated del(5q), lenalidomide can improve RBC transfusion dependence in most cases.⁵  Lenalidomide may also result in RBC-TI in approximately 25% of other MDS subtypes when combined with ESAs.⁶  Additionally, data suggest that the DNA methyltransferase inhibitors (DNMTis) azacitidine or decitabine can yield hematologic responses in lower-risk MDS, though typically using a different dosing schedule from that used in higher-risk MDS.⁷  Nonetheless, for a patient population that generally will live for years with their disease, new and more durable therapies are needed.

The treatment landscape for MDS changed recently with the approval of the activin receptor type IIB ligand trap luspatercept (ACE-536) following the results of the phase III MEDALIST trial (NCT02631070).⁸  The MEDALIST study randomized patients with RBC transfusion-dependent MDS with ring sideroblasts to receive luspatercept or placebo along with transfusion support. More patients in the luspatercept arm (38%) achieved RBC-TI lasting at least 8 weeks compared to those receiving placebo (13%). Subgroup analyses identified the best responders as those with fewer RBC transfusions and a lower erythropoietin level at baseline, suggesting that luspatercept might be more effective if administered earlier in the treatment of MDS.

These results set the stage for the COMMANDS trial, which randomizes patients with RBC transfusion-dependent LR-MDS (with or without ring sideroblasts) to EPO or luspatercept for the initial treatment of MDS. It uses several metrics that are more stringent than those used in other trials in MDS, including requiring a longer period of RBC-TI (12 vs. 8 weeks) that must be associated with a meaningful increase in hemoglobin levels (≥1.5 g/dL). At this point in follow-up, it has been reported that the luspatercept arm met the primary endpoint of a higher RBC-TI rate than in the EPO arm, although detailed data and information about secondary endpoints are yet to be reported.⁹ 

COMMENT: The COMMANDS trial represents an important paradigm shift in the management of patients with LR-MDS. Head-to-head treatment comparisons are lacking in LR-MDS, in part due to the paucity of active agents in this patient cohort.¹⁰  Without prospective data, it is difficult to determine which therapy should be used first in treating anemia in MDS, which is its most common associated morbidity.

Even given the initial encouraging data available from the COMMANDS trial, several questions remain, such as whether luspatercept should replace ESAs as the first-line treatment for RBC transfusion-dependent MDS. LR-MDS typically has a prolonged disease course, and thus the duration of responses and activity of second-line therapies are as important to understand as the frontline treatment responses. Moreover, no therapies to date in LR-MDS have been shown to prolong survival or delay progression to AML.

The COMMANDS trial comes at a time of increasing debate about the rationale for moving interventions for MDS earlier in disease presentation. Early initiation of ESAs (for example, prior to transfusion needs) may be associated with amelioration of anemia and decreased RBC transfusion burden, but it remains unclear whether this approach impacts patient survival, particularly in patients with relatively mild anemia.¹¹  Similar efforts have evaluated the role of early initiation of lenalidomide in patients with MDS with isolated del(5q). The Sintra-REV trial randomized patients with non–transfusion-dependent MDS to receive two years of lenalidomide or placebo, evaluating time to RBC transfusion dependence.¹²  The study showed that early initiation of lenalidomide delayed transfusion dependence compared to placebo, but there has been no significant difference in overall survival to date, raising the question of whether subjecting patients to early treatment is warranted if it does not modify their long-term outcomes. Nevertheless, any improvement in patient-reported outcomes and quality of life afforded by longer transfusion independence could justify such early treatment, even if unaccompanied by prolonged survival.

An important aspect of the COMMANDS study will be any subsequent information learned from the sequence of therapies in LR-MDS – particularly regarding second-line therapies received by each arm. For example, data suggest that lenalidomide administered after DNMTi therapy leads to lower response rates than if it is administered prior to DNMTi therapy.¹³  If patients will be considered for multiple lines of therapy over their disease course, we should strive for optimal sequencing of these to maximize response rates and durations at each step of the journey. Sequencing of therapies will also be important for clinical practice as we try to understand how future drugs, such as the telomerase inhibitor imetelstat (which is also being evaluated in transfusion-dependent LR-MDS), might be incorporated into the treatment algorithm.¹⁴ 

As risk-stratification in MDS becomes progressively refined (most recently with the introduction of the Molecular International Prognostic Scoring System, or IPSS-M, which incorporates molecular data),¹⁵  we should better be able to identify which patients are truly “lower-risk.” In such patients, MDS often behaves like a chronic illness, where patients live with their disease for many years. We need to understand not just what options are available, but also when they are most effective and meaningful to patient care and quality of life.