Roxadustat Combined With Luspatercept Versus Luspatercept Monotherapy in the Treatment of Refractory MDS-RS
Study Details
Study Description
Brief Summary
In a randomized controlled phase II/III clinical trial, 58% of patients with lower-risk MDS had at least a 50% reduction in red blood cell (RBC) transfusion units every 8 weeks after roxadustat treatment. In a randomized controlled phase III clinical trial, luspatercept significantly improved transfusion dependence in erythropoietin-stimulating agents (ESA)-refractory MDS-RS and improved hemoglobin response and quality of life, compared to placebo. This study aimed to evaluate the efficacy and safety of roxadustat combined with luspatercept versus luspatercept monotherapy in the treatment of refractory MDS-RS.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 4 |
Detailed Description
Myelodysplastic neoplasms (MDS) are heterogeneous clonal disorders of stem cells that result in peripheral blood cytopenia and ineffective hematopoiesis, with the potential risk of the development of acute myeloid leukemia (AML). Most patients with myelodysplastic syndromes with ring sideroblasts (MDS-RS) are stratified into lower-risk groups by the revised International Prognostic Scoring System (IPSS). At present, the main therapies for MDS-RS are red blood cell and platelet transfusion, erythropoietin (EPO), androgen, and iron chelation therapy. Roxadustat can up-regulate transferrin receptors to increase iron absorption, up-regulate transferrin to promote iron transport, and down-regulate ferritin levels to indirectly improve iron absorption and transport, promote plasma iron entry into the bone marrow to generate red blood cells and promote the production of EPO in the physiological range. Luspatercept generally promotes advanced erythrocyte maturation by inhibiting the TGF-β/smad2/3 signaling pathway. In a randomized controlled phase II/III clinical trial, 58% of patients with lower-risk MDS had at least a 50% reduction in red blood cell (RBC) transfusion units every 8 weeks after roxadustat treatment. In a randomized controlled phase III clinical trial, luspatercept significantly improved transfusion dependence in erythropoietin-stimulating agents (ESA)-refractory MDS-RS and improved hemoglobin response and quality of life, compared to placebo. The aim of this study was to evaluate the efficacy and safety of roxadustat combined with luspatercept versus luspatercept monotherapy in the treatment of refractory MDS-RS. If it is proved that the combination of the two drugs is better than luspatercept monotherapy, it can quickly improve the anemia of refractory MDS-RS and improve the quality of life.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: roxadustat and luspatercept Luspatercept (1.0 mg/kg, subcutaneously injection every 3 weeks, adjusted according to blood pattern, up to 1.75mg/kg. Roxadustat (150mgqod) was administered for at least 6 months to evaluate efficacy. Hemoglobin ≥120g/L can be discontinued, and hemoglobin <120g/L can continue to use. Those who are effective will continue to be given the combination therapy until ineffective or intolerant. |
Drug: Roxadustat
Roxadustat (150 mgqod)
Drug: Luspatercept
Luspatercept (1.0 mg/kg, subcutaneously injection every 3 weeks, adjusted according to blood pattern, up to 1.75mg/kg)
|
| Experimental: luspatercept Luspatercept (1.0 mg/kg, subcutaneously injection every 3 weeks, adjusted according to blood pattern, up to 1.75mg/kg. Luspatercept was given for at least 6 months to evaluate the efficacy. Hemoglobin ≥120g/L can be discontinued, and hemoglobin <120g/L can continue to use. Those who are effective will continue to be given the therapy until it is ineffective or intolerant |
Drug: Luspatercept
Luspatercept (1.0 mg/kg, subcutaneously injection every 3 weeks, adjusted according to blood pattern, up to 1.75mg/kg)
|
Outcome Measures
Primary Outcome Measures
- overall response rate (ORR) [6 month]
Proportion of patients who achieved complete response, partial response and hematological response.
Secondary Outcome Measures
- transfusion indenpendence (TI) [6 month]
Proportion of patients with transfusion dependence over 8 weeks
- adverse event rate [6 month]
Proportion of patients with adverse events
Eligibility Criteria
Criteria
Inclusion Criteria:
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Age >18 years old.
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Patients with a definite diagnosis of MDS-RS and stratified as lower-risk according to IPSS-R.
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After at least 6 weeks of rhEPO treatment, with hemoglobin<100g/L
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Adequate hepatic functions with alanine transaminase (ALT)/aspartate. transaminase (AST) levels within 2 times of the normal upper limit and total bilirubin levels within 2 times of the normal upper limit.
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ECOG≤2 with an expected life span of more than 6 months
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Documented patient consent.
Exclusion Criteria:
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Age <18 years old.
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Complicated with active or uncontrolled infections.
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Complicated with other malignancies.
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Creatinine/transaminase ≥ 2 normal upper limit.
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Complicated with myelofibrosis.
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Pregnant or lactating women, or men with recent fertility needs
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Allergic to luspatercept or excipients
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Patients with history of polysorbate 80 allergy
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Peking union medical college hospital | Beijing | China |
Sponsors and Collaborators
- Peking Union Medical College Hospital
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
- Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, Bloomfield CD, Cazzola M, Vardiman JW. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016 May 19;127(20):2391-405. doi: 10.1182/blood-2016-03-643544. Epub 2016 Apr 11.
- Attie KM, Allison MJ, McClure T, Boyd IE, Wilson DM, Pearsall AE, Sherman ML. A phase 1 study of ACE-536, a regulator of erythroid differentiation, in healthy volunteers. Am J Hematol. 2014 Jul;89(7):766-70. doi: 10.1002/ajh.23732. Epub 2014 Apr 26.
- Chen N, Hao C, Liu BC, Lin H, Wang C, Xing C, Liang X, Jiang G, Liu Z, Li X, Zuo L, Luo L, Wang J, Zhao MH, Liu Z, Cai GY, Hao L, Leong R, Wang C, Liu C, Neff T, Szczech L, Yu KP. Roxadustat Treatment for Anemia in Patients Undergoing Long-Term Dialysis. N Engl J Med. 2019 Sep 12;381(11):1011-1022. doi: 10.1056/NEJMoa1901713. Epub 2019 Jul 24.
- Crugliano G, Serra R, Ielapi N, Battaglia Y, Coppolino G, Bolignano D, Bracale UM, Pisani A, Faga T, Michael A, Provenzano M, Andreucci M. Hypoxia-Inducible Factor Stabilizers in End Stage Kidney Disease: "Can the Promise Be Kept?". Int J Mol Sci. 2021 Nov 22;22(22):12590. doi: 10.3390/ijms222212590.
- Feld J, Navada SC, Silverman LR. Myelo-deception: Luspatercept & TGF-Beta ligand traps in myeloid diseases & anemia. Leuk Res. 2020 Oct;97:106430. doi: 10.1016/j.leukres.2020.106430. Epub 2020 Jul 30.
- Fenaux P, Platzbecker U, Mufti GJ, Garcia-Manero G, Buckstein R, Santini V, Diez-Campelo M, Finelli C, Cazzola M, Ilhan O, Sekeres MA, Falantes JF, Arrizabalaga B, Salvi F, Giai V, Vyas P, Bowen D, Selleslag D, DeZern AE, Jurcic JG, Germing U, Gotze KS, Quesnel B, Beyne-Rauzy O, Cluzeau T, Voso MT, Mazure D, Vellenga E, Greenberg PL, Hellstrom-Lindberg E, Zeidan AM, Ades L, Verma A, Savona MR, Laadem A, Benzohra A, Zhang J, Rampersad A, Dunshee DR, Linde PG, Sherman ML, Komrokji RS, List AF. Luspatercept in Patients with Lower-Risk Myelodysplastic Syndromes. N Engl J Med. 2020 Jan 9;382(2):140-151. doi: 10.1056/NEJMoa1908892.
- Gupta N, Wish JB. Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors: A Potential New Treatment for Anemia in Patients With CKD. Am J Kidney Dis. 2017 Jun;69(6):815-826. doi: 10.1053/j.ajkd.2016.12.011. Epub 2017 Feb 24. Erratum In: Am J Kidney Dis. 2017 Jun;69(6):869.
- Henry DH, Glaspy J, Harrup R, Mittelman M, Zhou A, Carraway HE, Bradley C, Saha G, Modelska K, Bartels P, Leong R, Yu KP. Roxadustat for the treatment of anemia in patients with lower-risk myelodysplastic syndrome: Open-label, dose-selection, lead-in stage of a phase 3 study. Am J Hematol. 2022 Feb 1;97(2):174-184. doi: 10.1002/ajh.26397. Epub 2021 Nov 9.
- Komrokji RS, Platzbecker U, Fenaux P, Zeidan AM, Garcia-Manero G, Mufti GJ, Santini V, Diez-Campelo M, Finelli C, Jurcic JG, Greenberg PL, Sekeres MA, DeZern AE, Savona MR, Shetty JK, Ito R, Zhang G, Ha X, Backstrom JT, Verma A. Luspatercept for myelodysplastic syndromes/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis. Leukemia. 2022 May;36(5):1432-1435. doi: 10.1038/s41375-022-01521-4. Epub 2022 Feb 26. No abstract available.
- Kubasch AS, Fenaux P, Platzbecker U. Development of luspatercept to treat ineffective erythropoiesis. Blood Adv. 2021 Mar 9;5(5):1565-1575. doi: 10.1182/bloodadvances.2020002177.
- Markham A. Luspatercept: First Approval. Drugs. 2020 Jan;80(1):85-90. doi: 10.1007/s40265-019-01251-5.
- Suragani RN, Cadena SM, Cawley SM, Sako D, Mitchell D, Li R, Davies MV, Alexander MJ, Devine M, Loveday KS, Underwood KW, Grinberg AV, Quisel JD, Chopra R, Pearsall RS, Seehra J, Kumar R. Transforming growth factor-beta superfamily ligand trap ACE-536 corrects anemia by promoting late-stage erythropoiesis. Nat Med. 2014 Apr;20(4):408-14. doi: 10.1038/nm.3512. Epub 2014 Mar 23.
- Zheng Q, Yang H, Fu X, Huang Y, Wei R, Wang Y, Liu YN, Liu WJ. The efficacy and safety of roxadustat for anemia in patients with chronic kidney disease: a meta-analysis. Nephrol Dial Transplant. 2021 Aug 27;36(9):1603-1615. doi: 10.1093/ndt/gfaa110.
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