The treatment landscape for myelodysplastic syndromes (MDS) is rapidly evolving, marked by the emergence of novel targeted therapies and refined diagnostic criteria that leverage molecular features. These advancements promise to improve prognostic capabilities and offer viable treatment options, particularly for patients with low-risk disease. Andrew M. Brunner, MD, of Massachusetts General Hospital, highlighted these dynamic changes at the NCCN 2024 Annual Congress.
COMMANDS Trial Results
The phase 3 COMMANDS trial (NCT03682536) has significantly impacted the treatment paradigm for MDS. This trial evaluated luspatercept against the erythropoiesis-stimulating agent (ESA) epoetin alfa in 350 patients with very low-risk, low-risk, or intermediate-risk MDS. Patients were randomized to receive subcutaneous luspatercept (10.0 mg/kg, titrated up to 1.75 mg/kg every 3 weeks) or subcutaneous epoetin alfa (450 IU/kg, titrated up to 1050 IU/kg weekly). Patients previously treated with ESAs, disease-modifying agents, or hypomethylating drugs were excluded.
Notably, the adverse event (AE) profiles were closely monitored, given the low-risk nature of the patient population. While any-grade AEs were similar between the arms, the luspatercept arm (n = 178) showed higher rates of fatigue (15%), dyspnea (12%), and hypertension (13%) compared to the epoetin alfa arm (n = 176), where all three AEs occurred at a rate of 7%.
After 12 weeks, red blood cell transfusion independence significantly favored luspatercept over epoetin alfa by 1.5 g/dL (P < .0001). Responses were more frequent and durable in patients who were ring sideroblast (RS) positive compared to those who were RS negative.
These results build upon data from the phase 3 MEDALIST trial (NCT02631070), suggesting that luspatercept may salvage patients who require transfusions after epoetin alfa treatment. Brunner noted that the COMMANDS data indicate that luspatercept has a higher chance of achieving a response in the frontline setting compared to epoetin alfa, with potentially more durable outcomes.
According to NCCN guidelines, frontline options in low-risk MDS are stratified by RS status. Patients who are RS positive are candidates for frontline luspatercept, while those who are RS negative may be treated with epoetin alfa or darbepoetin alfa.
Emerging Therapies
Several novel therapies, including imetelstat (Rytelo) and ivosidenib (Tibsovo), are being evaluated in various treatment sequences. Imetelstat, in a phase 2/3 trial (NCT02598661) for patients with prior ESA treatment, demonstrated a 34% transfusion independence rate. Brunner emphasized that this rate was observed in patients who received more than 6 units of blood over 8 weeks, highlighting the potential for durable responses with imetelstat.
Imetelstat's use may also affect the clonal structure of the disease. Brunner explained that while the focus in low-risk disease has traditionally been on improving blood counts, there is increasing interest in modifying the disease course. Reducing mutation burden is now considered an important endpoint, correlating with the duration of transfusion independence.
The imetelstat drug label recommends weekly complete blood counts during the first two cycles and then every cycle thereafter, due to the potential for significant neutropenia and thrombocytopenia. In the IMerge trial, patients receiving imetelstat (n = 118) experienced treatment-emergent AEs (TEAEs) of any-grade thrombocytopenia (75%), neutropenia (74%), anemia (20%), and leukopenia (10%), compared to 10%, 7%, 10%, and 2%, respectively, in the placebo arm (n = 59).
Lenalidomide remains active in patients with low-risk disease who have isolated del(5q) or non-del(5q), particularly in combination with epoetin alfa. Additionally, ivosidenib has emerged as a treatment option for patients with relapsed or refractory MDS who have an IDH1 mutation.
Findings from the phase 3 SINTRA-REV trial (NCT01243476) confirmed that low-dose lenalidomide, when used to treat patients with low-risk MDS del(5q), prolonged the time to transfusion dependence from the beginning of treatment (66.6 vs 11.06 months), improved hemoglobin levels, and induced favorable quality clonal responses. Brunner noted that early lenalidomide administration can delay the time until patients require transfusions. Time to transfusion dependence was 66.3 months for patients in the lenalidomide arm and 11.6 months for the placebo arm (HR, 0.414; P = .021), though overall survival (OS) was not statistically significant between the two groups (P = .529).
Ivosidenib gained FDA approval in 2023 for relapsed or refractory MDS, demonstrating a complete remission rate of 39%. Some patients maintained OS for years, with a median OS of 36 months. Notable TEAEs include any-grade fatigue (15.8%), diarrhea (10.5%), and differentiation syndrome (10.5%).
Brunner concluded by emphasizing the increasing reliance on molecular assessment in MDS management. The challenge with IDH1 mutations is their relative rarity, affecting less than 5% of patients. However, identifying these mutations through sequencing panels can provide valuable therapeutic strategies. Overall, the management of MDS has evolved significantly, with more specific and precise diagnostic criteria and a growing emphasis on comprehensive molecular profiling.
