Addressing Second-Line Approaches in Low-Risk MDS
In a case discussion with Hetty Carraway, MD, MBA, associate professor of medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, in Ohio, PPO focused on clarifying how treatment goals differ between lower-risk and higher-risk myelodysplastic syndromes (MDS), with an emphasis on the priorities in lower-risk disease.
Overall, for lower-risk patients, the primary objective is to improve peripheral blood counts, particularly hemoglobin, while preventing complications such as bleeding and infections. Reducing the need for transfusions is highlighted as a central aim, since transfusion support is often the first intervention and can represent a substantial burden for patients.
According to Carraway, many individuals with MDS experience fatigue and other symptoms that significantly affect daily functioning. Therefore, alleviating symptoms and improving overall quality of life is a key therapeutic goal and can be highly meaningful for patients. A major challenge in the field has been accurately measuring these quality-of-life improvements through patient reported outcomes. Appropriate measures in MDS should be tailored to the disease, as the patient experience differs from other conditions. Factors such as transfusion dependence, the frequency of clinic visits, repeated laboratory testing, and the time required to receive transfusions all contribute to the overall burden and must be considered when evaluating outcomes.
The discussion centered around second-line therapy selection in a sample case and this is part 1 of a 2-part discussion of the case.
CASE SUMMARY
The patient was a 68-year-old female with low-risk MDS with symptomatic anemia.
- No del(5q) detected
- Ring sideroblasts: positive
- Laboratory findings
- White blood count: 2200/µL
- Absolute neutrophil count: 1200/µL
- Platelets: 108,000/µL
- Serum ferritin: 149 mcg/L
- Transferrin saturation: 23%
- Comorbidities:
- Mild chronic kidney disease (stage 2)
- Osteoarthritis
- Luspatercept-aamt (Reblozyl) was initiated and dose escalation was used, but hemoglobin level did not improve from 8.3 g/dL at 9 months.
- Red blood cell (RBC) transfusions were needed twice per month; patient is increasingly symptomatic (fatigue).
Targeted Oncology: What are the approaches in the second line if the patient develops resistance or is luspatercept refractory?
Hetty Carraway, MD, MBA: In patients with lower-risk MDS who have symptomatic anemia and don’t have a del(5q) mutation, and who relapse or are refractory to luspatercept, the preferred therapy is imetelstat (Rytelo). Other considerations include erythropoiesis-stimulating agents (ESAs) and granulocyte colony-stimulating factor (G-CSF), which is used primarily for treating anemia in lower-risk patients.
Santini V, et al1 have evaluated single-agent lenalidomide (Revlimid) in patients who are non-del(5q) but the likelihood of response is around 20% to 25% in that patient population.
Let’s turn to the phase 3 IMerge trial.2 In this study, 178 patients were enrolled. Approximately 62% of patients were ring sideroblast–positive and 38% were ring sideroblast–negative. There were no patients with del(5q) included. All participants had International Prognostic Scoring System low-or intermediate-risk disease. Patients either had a prior response to ESAs and were refractory or had relapsed, or they had a serum erythropoietin level greater than 500 U/L, indicating they were unlikely to respond to ESA-based therapy.
Participants were required to be transfusion dependent, defined as needing more than 4 units of RBCs over an 8-week period prior to being randomly assigned. Patients could not have received prior treatment with lenalidomide or hypomethylating agents. Eligibility criteria also required an absolute neutrophil count greater than 1500/µL and platelet count greater than 75,000/µL.
Patients were randomly assigned in a 2:1 fashion to receive imetelstat at 7.5 mg/kg every 4 weeks, with dose adjustments allowed for adverse events, or placebo given on the same schedule. Disease assessments occurred every 12 weeks after the first dose through week 72. Treatment was discontinued for disease progression, unacceptable toxicity, or withdrawal of consent, and crossover was not permitted.
The primary end point was RBC transfusion independence lasting at least 8 consecutive weeks. Key secondary end points included transfusion independence lasting 24 weeks, duration of transfusion independence, and rates of hematologic improvement.
Results showed that 40% of patients receiving imetelstat achieved at least 8 weeks of transfusion independence compared with 15% receiving placebo. Specifically, patients who received imetelstat demonstrated 51.6 weeks [range, 26.9-83.9] of RBC transfusion independence vs 13.3 weeks [range, 8.0-24.9] for patients in the control arm [HR, 0.23; 95% CI, 0.09-0.57; P = .007].2
Rates of independence at longer durations were 30% at 16 weeks, 28% at 24 weeks, and 18% at 1 year with imetelstat, compared with 7%, 3%, and minimal rates with placebo. Hemoglobin levels increased with imetelstat, while transfusion needs declined, with separation of response curves emerging around weeks 8 to 9.
What was the safety profile reported for imetelstat in the trial?
For many patients, there were reports of grade 3 and 4 hematologic toxicities. Specifically, grade 3 or 4 thrombocytopenia and neutropenia occurred in about 60%. Approximately 20% of patients experienced anemia, and 8% had leukopenia. In comparison, patients receiving placebo had about 10% rates of thrombocytopenia, neutropenia, and anemia, and 2% leukopenia.
With regard to gastrointestinal toxicities, these were minimal. There were very few grade 3 events, and no issues were observed with hyperbilirubinemia or headache.
In terms of treatment modifications, dose reductions due to adverse events occurred in about 49% of patients receiving imetelstat, and 16% of patients discontinued treatment due to adverse events.
Another common question is whether receiving this drug impacts progression to acute myeloid leukemia. The data showed that progression to AML was similar in the imetelstat group compared with patients receiving placebo.
What were the recommended dosing, monitoring, and dose modification strategies for imetelstat in the IMerge trial?
In discussing dosing of imetelstat, it is important to monitor blood counts prior to each dose and to check them weekly for the first two cycles, which corresponds to the first 8 weeks of therapy.3 During this time, complete blood counts should be reviewed and transfusion support provided as needed for cytopenias. After the first 2 cycles, monitoring can transition to monthly prior to each cycle. Liver function tests should also be obtained before each cycle, and supportive care for neutropenia or thrombocytopenia should be given as appropriate.
To reduce the risk of infusion-related reactions, patients should be premedicated 30 minutes before each dose with diphenhydramine and hydrocortisone. Patients should then be monitored for at least 1 hour after the infusion, as they should not leave immediately after receiving the drug.
The dosing is 7.1 mg/kg administered as a 2-hour intravenous infusion every 4 weeks, while the study dose was 7.5 mg/kg. Dose reductions may be required, with the first reduction to 5.6 mg/kg and the second to 4.4 mg/kg, typically to manage adverse events such as thrombocytopenia, neutropenia, or infusion related reactions. Dosing is based on actual body weight.
For grade 3 or 4 thrombocytopenia or neutropenia, treatment should be delayed until platelet counts recover to 50,000/µL, then resumed at the same dose, with subsequent recurrences prompting dose reduction. Similar approaches apply across severity levels. If infusion reactions occur, the infusion should be interrupted until symptoms resolve to grade 1 or lower, then restarted at 50% of the prior infusion rate. Comparable guidance applies to liver function test elevations.
Treatment should be discontinued if there is no reduction in red blood cell transfusion burden after 24 weeks, corresponding to 6 doses, or if unacceptable toxicity occurs, such as inability to tolerate the lowest dose or severe infusion reactions requiring hospitalization.
DISCLOSURES: Dr Carraway has received honoraria for advisory board memberships from AbbVie, Celgene/BMS, Genentech, Jazz Pharmaceuticals, Novartis, and Daiichi Sankyo; has received research funding from Celgene; has served on speakers bureau for BMS, Jazz Pharmaceuticals, Novartis, and Stemline Therapeutics; and has served on data safety monitoring boards for Astex, AbbVie, Takeda, and Syndax.
REFERENCES
Santini V, Giagounidis A, Pelligra CG, et al. Impact of lenalidomide treatment on overall survival in patients with lower-risk, transfusion-dependent myelodysplastic syndromes. Clin Lymphoma Myeloma Leuk. 2022;22(9):e874-e883. doi:10.1016/j.clml.2022.05.001
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
Rytelo. Prescribing information. Geron; 2024. Accessed February 24, 2026.
https://tinyurl.com/3wndc237
