Effect of Luspatercept Treatment in Patients with MDS/MPN-RS-T

MDS/MPN-RS-T

Myelodysplastic syndrome/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) is a myeloid disease with both dysplastic and myeloproliferative features. Anemia associated with this disease causes fatigue, reduces quality of life, and shortens patients' survival.

Patients with MDS/MPN-RS-T have a better prognosis compared to patients with myelodysplastic syndrome with ring sideroblasts (MDS-RS), but approximately half of them require repeated red blood cell transfusions. Patients with MDS/MPN-RS-T also have about a 4-fold higher risk of thrombosis compared to those with MDS-RS.

Treatment of MDS/MPN-RS-T focuses on alleviating anemia, reducing thrombotic risk, lowering platelet count, and overall influencing the disease course. Luspatercept is a drug that, by binding to transforming growth factor-beta (TGF-β) class ligands, affects erythrocyte maturation.

The results of the phase III MEDALIST study supported the approval of luspatercept for treating anemia in adult patients with lower-risk myelodysplastic syndrome with ring sideroblasts (MDS-RS) or MDS/MPN-RS-T who need ≥ 2 red blood cell units in 8 weeks after the failure of erythropoiesis-stimulating agents (ESA).

Post hoc Analysis in MDS/MPN-RS-T

The results of the post hoc analysis of the MEDALIST study focusing on patients with MDS/MPN-RS-T were published in the journal Leukemia in 2022.

In this study, patients refractory to or intolerant of ESA were randomized in a 2:1 ratio to receive either luspatercept or placebo, administered subcutaneously every 3 weeks for 24 weeks. The starting dose of luspatercept was 1.0 mg/kg with further titration to a maximum dose of 1.75 mg/kg based on transfusion requirements and occurrence of adverse events.

The primary study endpoint was defined as achieving red blood cell transfusion independence (RBC-TI) for at least 8 weeks in weeks 1–24. Secondary endpoints included modified hematologic improvement in erythroid lineage (mHI-E; with an average hemoglobin increase of at least 15 g/l in patients needing < 4 red blood cell units/8 weeks), reduction of transfusion requirements by ≥ 4 units (in patients with higher transfusion needs over 56 consecutive days), incidence of progression to AML, and occurrence of adverse events.

The post hoc analysis also included an assessment of clinical benefit (i.e., RBC-TI for at least 8 weeks and/or mHI-E during weeks 1–24).

Results

Of the 229 patients enrolled in the study, 23 (10%) had an MDS/MPN-RS-T diagnosis, with 14 randomized to receive luspatercept and 9 placebo. Initial differences between groups were noted in leukocyte counts (48 × 10⁹/l for luspatercept vs. 75 × 10⁹/l for placebo), serum ferritin levels (10,620 vs. 14,600 μg/l), and erythropoietin levels (71.9 vs. 54.0 U/l). The median follow-up for patients treated with luspatercept was 27.4 months (range 3.5–35.6), compared to 13.8 months (3.3–32.2) in the placebo group.

In the cut-off analysis of July 2019, a significantly higher proportion of patients treated with luspatercept achieved RBC-TI ≥ 8 weeks during weeks 1–24 compared to placebo (64.3% vs. 22.2%; p = 0.028), mHI-E (71.4% vs. 11.1%; p = 0.006), and clinical benefit (78.6% vs. 33.3%; p = 0.034). The median duration from clinical benefit onset to treatment termination was 94.6 weeks (range 8.0–150.0) for luspatercept versus 23.9 weeks (23.7–57.9) for placebo.

In patients with lower transfusion burdens (< 4 units over 8 weeks), luspatercept treatment led to numerically more frequent achievement of RBC-TI ≥ 8 weeks in weeks 1–24 (83.3% vs. 50.0%; p = 0.285) and significantly higher mHI-E (66.7% vs. 0.0%; p = 0.046) compared to placebo. For patients with higher transfusion burdens (≥ 4 units/8 weeks), both differences were numerically distinct but did not reach statistical significance (RBC-TI: 50.0% vs. 0.0%; p = 0.068; mHI-E: 75.0% vs. 20.0%; p = 0.063).

Over a longer term of 48 weeks, RBC-TI ≥ 8 weeks was achieved by 64.3% of patients randomized to the luspatercept arm compared to 33.3% in the placebo group (p = 0.088). Very long-term effects, i.e., RBC-TI ≥ 48 weeks at any time during treatment, were achieved by 28.6% of luspatercept patients and none in the placebo group.

The most common adverse events associated with treatment were dizziness, nausea, diarrhea, or asthenia. Adverse events led to treatment discontinuation in 14.3% of luspatercept patients and 33.3% of placebo patients. One patient in the luspatercept group experienced a transient ischemic attack during treatment. Only one patient in the placebo group progressed to AML, and none in the luspatercept group.

Conclusion

Despite the low number of participants, the results of the MEDALIST study indicate that luspatercept may provide a clinical benefit to patients with MDS/MPN-RS-T. This is an important finding as there are currently no effective treatment options for this patient group verified in prospective clinical trials. This analysis showed luspatercept to be effective in reducing transfusion burden and increasing hemoglobin levels, as well as being well-tolerated.

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Source: Komrokji R. S., Platzbecker U., Fienaux P. et al., Luspatercept for myelodysplastic syndromes/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis, Leukemia 2022; 36 (5): 1432–1435, doi: 10.1038/s41375-022-01521-4.