Abstract: Patients with myelodysplastic syndromes (MDS) collectively have a high symptom burden and are also at risk of death from complications of cytopenias and acute myeloid leukemia. The goals of therapy for patients with MDS are to reduce disease-associated symptoms and the risk of disease progression and death, thereby improving both quality and quantity of life. Treatment is based on the type of MDS, MDS risk group, and other factors, as well as patient age and overall health. Often more than one type of treatment is used. This article discusses the novel MDS therapies in development, with a focus on those that seem most likely to reach regulatory approval.
Treatment options for patients with myelodysplastic syndromes (MDS) remain fairly limited. Per National Comprehensive Cancer Center Network guidelines, current therapies include lenalidomide, growth factors, hypomethylating agents (HMA), and allogeneic hematopoietic cell transplant (allo-HCT).1 Despite years of therapeutic stagnation, several promising agents have recently emerged as front runners for potential approval, hopefully breaking the 10-year drought in approvals for this disease. These include luspatercept, rigosertib, splicing inhibitors, IDH inhibitors, and small molecules targeting apoptosis. Despite the historical failure of combination strategies in MDS, recent data with novel combinations and “enhanced” DNA methyltransferase inhibitors such as guadecitabine show promise. A cautious optimism is emerging about the future of novel MDS therapies. Here we summarize some recent advances in the management of patients with MDS.
Current State of MDS and Standard Treatment Practices
MDS refers to a heterogenous group of myeloid disorders characterized by somatically mutated hematopoietic stem cells, the presence of variable peripheral cytopenias, and a broad risk of progression to acute myeloid leukemia (AML).2 MDS is most prevalent in older adults, with the median age at diagnosis ranging between age 70 and 75 years.1 The incidence of MDS in the United States increases exponentially from age 40 where the rate is 0.2 per 100,000 people, to age 85 where there are 45 cases of MDS per 100,000 people.2 Currently there are approximately 10,000 to 15,000 new cases of MDS diagnosed annually in the United States. The exact number of new cases is unknown; however, the incidence is believed to be increasing.3 With the aging demographic of the US population, the incidence of MDS and AML are likely to increase.
Despite an improved understanding of disease biology in MDS, novel therapeutics have been limited. No new drugs for MDS have been approved in the last 10 years. Growth factors, immunosuppressive therapy, and lenalidomide are the standard of care for lower risk MDS, while hypomethylating agents, ie, azacitidine and decitabine, as well as allo-HCT remain the standard of care for higher risk patients.2 For those who fail to respond to the standard of care, outcomes are dismal.4 There is a guarded optimism owing to data from promising early phase trials as well as a phase 3 trial in low-risk disease in the management of MDS. There remains a pressing need to enroll patients in therapeutic MDS clinical trials to alter the current stagnation in approved therapies. Stringent inclusion criteria of clinical trials pose a challenge to MDS clinical trials accrual, as typical MDS patients are older in age and often have comorbidities. Figure 1 depicts a snapshot of current treatment pathway for MDS management.
In this article, we will discuss the novel MDS therapies in development, with a focus on those that seem most likely to reach regulatory approval.
Novel Therapies in the Pipeline
Lower Risk MDS
Luspatercept (ACE-536) is a modified activin receptor IIB-IgG Fc fusion protein that targets transforming growth factor beta (TGF-B) signaling via Smad2/3 and growth and differentiation factor 11 (GDF-11) enhances late-stage red blood cell (RBC) maturation.5 ACE-536 was investigated in patients with lower risk MDS; this agent was developed for transfusion-dependent, anemic patients who do not meet criteria for erythropoiesis stimulating agents (ESA) therapy or who have failed to respond to such treatment (Figure 1).6 In practice, this agent has shown the most promise for patients with ringed sideroblasts (RS), particularly those harboring mutant SF3B1. In a phase 2 trial, PACE-MDS, examining the safety and efficacy of luspatercept, 63% of the 51 patients treated with higher-dose luspatercept achieved hematological improvement-erythroid (HI-E), and 38% of 42 patients eligible for RBC transfusion independence (RBC-TI) achieved RBC-TI.6 The PACE-MDS study also revealed a significant response among patients with RS levels of at least 15% and SF3B1 mutations; 69% and 77% achieved HI-E, respectively.6 Recently, a randomized, double-blinded, phase 3 trial (MEDALIST) enrolled participants with lower risk MDS with RS with the primary endpoint of RBC-TI for at least 8 weeks.7 A total of 229 patients received luspatercept 1 mg/kg subcutaneously every 21 days or placebo in a 2:1 randomized fashion. Of the 153 patients who received luspatercept, 58 participants (38%) met the primary endpoint of RBC-TI compared with 10 participants (13%) in the placebo group with a mean hemoglobin of >1.5 g/dL for 8 weeks (P <.0001).7 Most common treatment-related adverse events (AEs) included fatigue, dizziness, asthenia, and diarrhea.7 Luspatercept is currently under Food and Drug Administration (FDA) review for approval in lower risk MDS with RS.
Imetelstat is a telomerase inhibitor currently being studied for lower risk MDS patients who are transfusion-dependent and have failed with ESA. In a prior study, myelofibrosis patients on imetelstat had achieved complete responses in the setting of U2AF1 or SF3B1 mutations.8 The IMerge study, a phase 2/3 clinical trial, focused on lower risk MDS patients who were transfusion-dependent as well as refractory to ESA and naïve to lenalidomide and/or HMA.9 The rates of 8- and 24-week TI were 37% and 26%, respectively.9 The 24-week TI responses were accompanied by a rise in hemoglobin of at least 3 g/dL, and the HI-E rate was 71%.9 The side effects were mostly related to cytopenias. The phase 3 part of the study is soon to begin patient enrollment.9
Iron chelation therapy is a key component of managing lower risk MDS patients with transfusion requirement. The randomized, double-blind, phase 2 TELESTO trial evaluated the safety and efficacy of deferasirox vs placebo in 225 adults diagnosed with low/intermediate-1 MDS who had iron overload.10 The primary endpoint was an event defined as a composite of liver function abnormalities, cardiac abnormalities, transformation to AML, or death. Participants were required to have a significant transfusion history, an elevated serum ferritin, and be free from cardiac, liver, and renal abnormalities. Patients in the deferasirox group experienced significantly longer median event-free survival compared with the placebo group; 1440 days vs 1091 days (P=.01).10 However, the median overall survival (OS) was not significantly different between the two groups. The rate of all severe AEs was comparable in both groups.10 Despite lack of survival advantage, specific subsets of MDS patients with high transfusion burden might benefit from iron chelation.