Luspatercept, Improved Diagnostics Deliver in MDS

The management of myelodysplastic syndromes (MDS) has evolved significantly in recent years with the emergence of novel, targeted therapies and improved diagnostic criteria leveraged by a greater reliance on molecular features. A shift in a greater understanding of molecular genetics has led to improved prognostic capabilities in MDS. In particular, clinicians now have a viable treatment option for patients with low-risk disease, helping them better predict disease trajectory.

“We have seen a number of dynamic changes in MDS over the last few years, and integrating them into our treatment paradigm will impact our approach, and perhaps offer a glimpse into the future,” Andrew M. Brunner, MD, associate professor of medicine, Massachusetts General Hospital, Boston, Massachusetts, said during his presentation at the NCCN 2024 Annual Congress.¹

COMMANDS Trial

The latest development in the treatment landscape for MDS has been the findings from the phase 3 COMMANDS trial (NCT03682536; VISUAL SYNOPSIS). Investigators evaluated luspatercept vs the erythropoiesis-stimulating agent (ESA) epoetin alfa in 350 patients with very low-risk, low-risk, or intermediate-risk MDS.

Patients were randomly assigned to receive subcutaneous luspatercept once every 3 weeks at 10.0 mg/kg body weight, with possible titration up to 1.75 mg/kg vs subcutaneous epoetin alfa once a week starting at 450 IU/kg per body weight with possible titration up to 1050 IU/kg.² Patients were ineligible if they were treated with prior ESAs; disease-modifying agents; or hypomethylating drugs.

Because patients had low-risk disease, investigators paid close attention to the adverse events (AEs) profile. They noted that any-grade AEs for both arms were similar, although patients in the luspatercept arm (n = 178) had higher rates of anygrade fatigue (15%), dyspnea (12%), and hypertension (13%) compared with those in the epoetin alfa arm (n = 176; 7% for all 3 AE types), respectively.²

Further, after 12 weeks, red blood cell transfusion independence favored patients who received luspatercept vs epoetin alfa by 1.5 g/dL (P < .0001).² Responses were more frequent and more durable in patients who were ring sideroblast (RS) positive vs those who were RS negative.

Results from COMMANDS also advance the discussion on sequencing with regard to these agents. Data from the phase 3 MEDALIST trial (NCT02631070) suggest that if the patient requires a transfusion after receiving epoetin alfa, a switch to luspatercept might lead to salvaging those patients and restore their independence from needing transfusions.

“But now we have these data [from COMMANDS] suggesting that in the front line, luspatercept has a higher chance of getting a response compared with epoetin alfa, and that response might be durable,” Brunner said.

According to NCCN guidelines,³ frontline options in low-risk MDS are stratified by the presence or absence of RS. Patients who are RS positive are candidates for frontline luspatercept. Patients who are RS negative are candidates for epoetin alfa or darbepoetin alfa.

Additional Novel Therapies

A number of novel therapies, including imetelstat (Rytelo) and ivosidenib (Tibsovo), have been evaluated with subsequent treatment sequence strategies also explored. Imetelstat demonstrated promise in a phase 2/3 trial (NCT02598661) for patients with prior ESA treatment, showing a 34% transfusion independence rate.⁴

“What was notable from the findings was that rate was seen in patients who received greater than 6 units of blood over 8 weeks,” Brunner said. “That emphasizes that patients exhibited durable responses when using imetelstat,” he continued.

Brunner pointed out that the use of imetelstat could affect the clonal structure of the disease. “In low-risk disease, the emphasis for a long time has been on getting better blood counts for the patient, improving their hemoglobin levels,” he said. “But now, we’re asking [whether] we can actually modify the course of the disease. One of the end points that we’re now considering is reducing mutation burden in these patients. That reduction in mutation burden seems to correlate with the duration of transfusion independence,” Brunner said.

The drug label for imetelstat recommends weekly complete blood counts during the first 2 cycles and then every cycle thereafter, as neutropenia and thrombocytopenia can be fairly significant during the course of treatment. According to Platzbecker et al,⁴ patients receiving imetelstat (n = 118) experienced treatment-emergent AEs (TEAEs) of any-grade thrombocytopenia (75%), neutropenia (74%), anemia (20%), and leukopenia (10%). In contrast, patients in the placebo arm (n = 59) experienced TEAEs of any grade of 10%, 7%, 10%, and 2%, respectively.

Brunner said that lenalidomide remains active in patients with low-risk disease who have isolated del(5q) or non del(5q), particularly in combination with epoetin alfa. In addition, 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)5 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.

“This study showed that giving early lenalidomide to patients prior to transfusion dependence can delay the time until patients start to need transfusions,” Brunner said.

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). Brunner noted that overall survival (OS) was not statistically significant between the 2 treatment groups (P = .529).

Ivosidenib gained FDA approval in 2023 for relapsed or refractory MDS with a complete remission rate of 39%.6 Investigators reported that some patients’ OS could be maintained for years, with a median OS of 36 months.⁷

TEAEs of note include any-grade fatigue (15.8%), diarrhea (10.5%), and differentiation syndrome (10.5%).⁷

“The challenge with IDH1 mutations is that it is relatively rare in MDS. It affects less than 5% of patients. It can be identified through the use of sequencing panels. This can be a boon to a therapeutic strategy. Overall, the management of MDS has evolved in the last 5 to 10 years and our criteria to define what MDS is has become much more specific and precise, with a growing reliance on full molecular assessment,” Brunner said.

REFERENCES:

1. Brunner AM. Myelodysplastic syndromes: treatment updates and emerging data. Presented at: NCCN 2024 Annual Congress; September 20-21, 2024; New York, NY.

2. Platzbecker U, Della Porta MG, Santini V, et al. Efficacy and safety of luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, transfusion-dependent, lower-risk myelodysplastic syndromes (COMMANDS): interim analysis of a phase 3, open-label, randomised controlled trial. Lancet. 2023;402(10399):373-385. doi:10.1016/S01406736(23)00874-7

3. NCCN. Clinical Practice Guidelines in Oncology. Myeloproliferative neoplasms, version 2.2024. Accessed September 26, 2024. https://tinyurl.com/2bh7w4u5

4. Platzbecker U, Santini V, Fenaux P, et al. Imetelstat in patients with lower-risk myelodysplastic syndromes who have relapsed or are refractory to erythropoiesis-stimulating agents (IMerge): a multinational, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2024;403(10423):249-260. doi:10.1016/ S0140-6736(23)01724-5

5. Cadenas FL, Lumbreras E, González T, et al. Evaluation of lenalidomide (LEN) vs placebo in non-transfusion dependent low risk del(5q) MDS patients: final results of Sintra-REV phase III international multicenter clinical trial. Blood. 2022;140 (suppl 1):1109-1111. doi:10.1182/blood-2022-168718

6. FDA approves ivosidenib for myelodysplastic syndromes. FDA. October 24, 2023. Accessed September 27, 2024. https:// tinyurl.com/383zb9sw

7. DiNardo CD, Roboz GJ, Watts JM, et al. Final phase 1 substudy results of ivosidenib for patients with mutant IDH1 relapsed/refractory myelodysplastic syndrome. Blood Adv. 2024;8(15):4209-4220. doi:10.1182/bloodadvances.2023012302