Vol 11, No 4 (2020)
Review paper
Published online: 2021-03-30

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A therapeutic approach to lower-risk myelodysplastic syndromes

Kamil Wiśniewski1, Aleksandra Gołos2, Joanna Góra-Tybor3
Hematologia 2020;11(4):219-234.

Abstract

Myelodysplastic syndromes (MDS) are acquired clonal disorders of the hematopoietic system caused by a mutation in hematopoietic stem cells. Depending on clinical and laboratory parameters, MDS is divided into two subgroups: low-risk MDS (LR-MDS) and high-risk MDS (HR-MDS), which determines a range of therapeutic options. Recently, some progress in prolongation and quality of life has been observed, mainly due to new therapeutic and supportive methods. The article provides an overview of the current diagnostic and therapeutic approach to lower-risk MDS, as well as manifests the most recent registered therapeutic methods. Additionally, the paper reviews supportive treatment and drugs in clinical trials.

 

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References

  1. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016; 127(20): 2391–2405.
  2. Platzbecker U. Treatment of MDS. Blood. 2019; 133(10): 1096–1107.
  3. Steensma DP. Myelodysplastic syndromes current treatment algorithm 2018. Blood Cancer J. 2018; 8(5): 47.
  4. Valent P, Orazi A, Steensma DP, et al. Proposed minimal diagnostic criteria for myelodysplastic syndromes (MDS) and potential pre-MDS conditions. Oncotarget. 2017; 8(43): 73483–73500.
  5. Solé F, Espinet B, Sanz GF, et al. Incidence, characterization and prognostic significance of chromosomal abnormalities in 640 patients with primary myelodysplastic syndromes. Grupo Cooperativo Español de Citogenética Hematológica. Br J Haematol. 2000; 108(2): 346–356.
  6. Visconte V, Tiu RV, Rogers HJ. Pathogenesis of myelodysplastic syndromes: an overview of molecular and non-molecular aspects of the disease. Blood Res. 2014; 49(4): 216–227.
  7. Le Beau MM, Albain KS, Larson RA, et al. Clinical and cytogenetic correlations in 63 patients with therapy-related myelodysplastic syndromes and acute nonlymphocytic leukemia: further evidence for characteristic abnormalities of chromosomes no. 5 and 7. J Clin Oncol. 1986; 4(3): 325–345.
  8. Hosono N. Genetic abnormalities and pathophysiology of MDS. Int J Clin Oncol. 2019; 24(8): 885–892.
  9. Mossner M, Jann JC, Nowak D, et al. Prevalence, clonal dynamics and clinical impact of TP53 mutations in patients with myelodysplastic syndrome with isolated deletion (5q) treated with lenalidomide: results from a prospective multicenter study of the german MDS study group (GMDS). Leukemia. 2016; 30(9): 1956–1959.
  10. DiNardo CD, Watts J, Stein E, et al. Ivosidenib (AG-120) induced durable remissions and transfusion independence in patients with IDH1-mutant relapsed or refractory myelodysplastic syndrome: results from a phase 1 dose escalation and expansion study. Blood. 2018; 132(Suppl 1): 1812–1812.
  11. Richard-Carpentier G, DeZern A, Takahashi K, et al. Preliminary results from the phase II study of the IDH2-inhibitor enasidenib in patients with high-risk IDH2-mutated myelodysplastic syndromes (MDS). Blood. 2019; 134(Suppl_1): 678–678.
  12. Greenberg P, Cox C, LeBeau M, et al. International Scoring System for evaluating prognosis in myelodysplastic syndromes. Blood. 1997; 89(6): 2079–2088.
  13. Greenberg PL, Tuechler H, Schanz J, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012; 120(12): 2454–2465.
  14. Malcovati L, Porta MG, Pascutto C, et al. Prognostic factors and life expectancy in myelodysplastic syndromes classified according to WHO criteria: a basis for clinical decision making. J Clin Oncol. 2005; 23(30): 7594–7603.
  15. Moreno Berggren D, Folkvaljon Y, Engvall M, et al. Prognostic scoring systems for myelodysplastic syndromes (MDS) in a population-based setting: a report from the Swedish MDS register. Br J Haematol. 2018; 181(5): 614–627.
  16. Neukirchen J, Schoonen WM, Strupp C, et al. Incidence and prevalence of myelodysplastic syndromes: data from the Düsseldorf MDS-registry. Leuk Res. 2011; 35(12): 1591–1596.
  17. Jaeger M, Aul C, Söhngen D, et al. [Secondary hemochromatosis in polytransfused patients with myelodysplastic syndromes] [Article in German]. Beitr Infusionsther. 1992; 30: 464–468.
  18. Fenaux P, Platzbecker U, Ades L. How we manage adults with myelodysplastic syndrome. Br J Haematol. 2020; 189(6): 1016–1027.
  19. Hellström-Lindberg E, Tobiasson M, Greenberg P. Myelodysplastic syndromes: moving towards personalized management. Haematologica. 2020; 105(7): 1765–1779.
  20. Fenaux P, Santini V, Spiriti MA, et al. A phase 3 randomized, placebo-controlled study assessing the efficacy and safety of epoetin-α in anemic patients with low-risk MDS. Leukemia. 2018; 32(12): 2648–2658.
  21. Platzbecker U, Symeonidis A, Oliva EN, et al. A phase 3 randomized placebo-controlled trial of darbepoetin alfa in patients with anemia and lower-risk myelodysplastic syndromes. Leukemia. 2017; 31(9): 1944–1950.
  22. Park S, Kelaidi C, Meunier M, et al. The prognostic value of serum erythropoietin in patients with lower-risk myelodysplastic syndromes: a review of the literature and expert opinion. Ann Hematol. 2020; 99(1): 7–19.
  23. Santini V, Schemenau J, Levis A, et al. Can the revised IPSS predict response to erythropoietic-stimulating agents in patients with classical IPSS low or intermediate-1 MDS? Blood. 2013; 122(13): 2286–2288.
  24. Houston BL, Jayakar J, Wells RA, et al. A predictive model of response to erythropoietin stimulating agents in myelodysplastic syndrome: from the Canadian MDS patient registry. Ann Hematol. 2017; 96(12): 2025–2029.
  25. Malcovati L, Hellström-Lindberg E, Bowen D, et al. European Leukemia Net. Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet. Blood. 2013; 122(17): 2943–2964.
  26. Garcia-Manero G, Chien KS, Montalban-Bravo G. Myelodysplastic syndromes: 2021 update on diagnosis, risk stratification and management. Am J Hematol. 2020; 95(11): 1399–1420.
  27. Greenberg PL, Sun Z, Miller KB, et al. Treatment of myelodysplastic syndrome patients with erythropoietin with or without granulocyte colony-stimulating factor: results of a prospective randomized phase 3 trial by the Eastern Cooperative Oncology Group (E1996). Blood. 2009; 114(12): 2393–2400.
  28. Hellström-Lindberg E, Birgegård G, Carlsson M, et al. A combination of granulocyte colony-stimulating factor and erythropoietin may synergistically improve the anaemia in patients with myelodysplastic syndromes. Leuk Lymphoma. 1993; 11(3-4): 221–228.
  29. Jädersten M, Malcovati L, Dybedal I, et al. Erythropoietin and granulocyte-colony stimulating factor treatment associated with improved survival in myelodysplastic syndrome. J Clin Oncol. 2008; 26(21): 3607–3613.
  30. List A, Dewald G, Bennett J, et al. Myelodysplastic Syndrome-003 Study Investigators. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med. 2006; 355(14): 1456–1465.
  31. Santini V, Almeida A, Giagounidis A, et al. Randomized phase III study of lenalidomide versus placebo in RBC transfusion-dependent patients with lower-risk non-del(5q) myelodysplastic syndromes and ineligible for or refractory to erythropoiesis-stimulating agents. J Clin Oncol. 2016; 34(25): 2988–2996.
  32. Sibon D, Cannas G, Baracco F, et al. Groupe Francophone des Myélodysplasies. Lenalidomide in lower-risk myelodysplastic syndromes with karyotypes other than deletion 5q and refractory to erythropoiesis-stimulating agents. Br J Haematol. 2012; 156(5): 619–625.
  33. Narla A, Dutt S, McAuley JR, et al. Dexamethasone and lenalidomide have distinct functional effects on erythropoiesis. Blood. 2011; 118(8): 2296–2304.
  34. McGraw KL, Basiorka AA, Johnson JO, et al. Lenalidomide induces lipid raft assembly to enhance erythropoietin receptor signaling in myelodysplastic syndrome progenitors. PLoS One. 2014; 9(12): e114249.
  35. Adema V, Palomo L, Toma A, et al. Groupe Francophone des Myélodysplasies. A G polymorphism in the CRBN gene acts as a biomarker of response to treatment with lenalidomide in low/int-1 risk MDS without del(5q). Leukemia. 2013; 27(7): 1610–1613.
  36. Komrokji RS. Activin receptor II ligand traps: new treatment paradigm for low-risk MDS. Curr Hematol Malig Rep. 2019; 14(4): 346–351.
  37. Komrokji RS. Luspatercept in myelodysplastic syndromes: who and when? Hematol Oncol Clin North Am. 2020; 34(2): 393–400.
  38. Platzbecker U, Germing U, Götze KS, et al. Luspatercept for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes (PACE-MDS): a multicentre, open-label phase 2 dose-finding study with long-term extension study. Lancet Oncol. 2017; 18(10): 1338–1347.
  39. Fenaux P, Platzbecker U, Mufti GJ, et al. Luspatercept in patients with lower-risk myelodysplastic syndromes. N Engl J Med. 2020; 382(2): 140–151.
  40. Kantarjian H, Issa JPJ, Rosenfeld CS, et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer. 2006; 106(8): 1794–1803.
  41. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. International Vidaza High-Risk MDS Survival Study Group. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009; 10(3): 223–232.
  42. Musto P, Maurillo L, Spagnoli A, et al. Ad Hoc Italian Cooperative Study Group on Azacitidine in Myelodysplastic Syndromes Acute Leukemias. Azacitidine for the treatment of lower risk myelodysplastic syndromes: a retrospective study of 74 patients enrolled in an Italian named patient program. Cancer. 2010; 116(6): 1485–1494.
  43. Sanchez-Garcia J, Falantes J, Medina Perez A, et al. Grupo Andaluz SMD. Prospective randomized trial of 5 days azacitidine versus supportive care in patients with lower-risk myelodysplastic syndromes without 5q deletion and transfusion-dependent anemia. Leuk Lymphoma. 2018; 59(5): 1095–1104.
  44. Garcia-Manero G, Jabbour E, Borthakur G, et al. Randomized open-label phase II study of decitabine in patients with low- or intermediate-risk myelodysplastic syndromes. J Clin Oncol. 2013; 31(20): 2548–2553.
  45. Jabbour E, Short NJ, Montalban-Bravo G, et al. Randomized phase 2 study of low-dose decitabine vs low-dose azacitidine in lower-risk MDS and MDS/MPN. Blood. 2017; 130(13): 1514–1522.
  46. Grinblatt DL, Sekeres MA, Komrokji RS, et al. Patients with myelodysplastic syndromes treated with azacitidine in clinical practice: the AVIDA registry. Leuk Lymphoma. 2015; 56(4): 887–895.
  47. Tobiasson M, Dybedahl I, Holm MS, et al. Limited clinical efficacy of azacitidine in transfusion-dependent, growth factor-resistant, low- and Int-1-risk MDS: Results from the nordic NMDSG08A phase II trial. Blood Cancer J. 2014; 4: e189.
  48. Houwerzijl EJ, Blom NR, van der Want JJL, et al. Increased peripheral platelet destruction and caspase-3-independent programmed cell death of bone marrow megakaryocytes in myelodysplastic patients. Blood. 2005; 105(9): 3472–3479.
  49. Tamura H, Ogata K, Luo S, et al. Plasma thrombopoietin (TPO) levels and expression of TPO receptor on platelets in patients with myelodysplastic syndromes. Br J Haematol. 1998; 103(3): 778–784.
  50. Fenaux P, Muus P, Kantarjian H, et al. Romiplostim monotherapy in thrombocytopenic patients with myelodysplastic syndromes: long-term safety and efficacy. Br J Haematol. 2017; 178(6): 906–913.
  51. Kantarjian H, Fenaux P, Sekeres MA, et al. Safety and efficacy of romiplostim in patients with lower-risk myelodysplastic syndrome and thrombocytopenia. J Clin Oncol. 2010; 28(3): 437–444.
  52. Kantarjian HM, Sekeres MA, Ribrag V, et al. Subcutaneous or intravenous administration of romiplostim in thrombocytopenic patients with lower risk myelodysplastic syndromes. Cancer. 2011; 117(5): 992–1000.
  53. Sekeres MA, Giagounidis A, Kantarjian H, et al. Development and validation of a model to predict platelet response to romiplostim in patients with lower-risk myelodysplastic syndromes. Br J Haematol. 2014; 167(3): 337–345.
  54. Oliva EN, Alati C, Santini V, et al. Eltrombopag versus placebo for low-risk myelodysplastic syndromes with thrombocytopenia (EQoL-MDS): phase 1 results of a single-blind, randomised, controlled, phase 2 superiority trial. Lancet Haematol. 2017; 4(3): e127–e136.
  55. Corazza F, Hermans C, D'Hondt S, et al. Circulating thrombopoietin as an in vivo growth factor for blast cells in acute myeloid leukemia. Blood. 2006; 107(6): 2525–2530.
  56. Kantarjian HM, Fenaux P, Sekeres MA, et al. Long-term follow-up for up to 5 years on the risk of leukaemic progression in thrombocytopenic patients with lower-risk myelodysplastic syndromes treated with romiplostim or placebo in a randomised double-blind trial. Lancet Haematol. 2018; 5(3): e117–e126.
  57. Prica A, Sholzberg M, Buckstein R. Safety and efficacy of thrombopoietin-receptor agonists in myelodysplastic syndromes: a systematic review and meta-analysis of randomized controlled trials. Br J Haematol. 2014; 167(5): 626–638.
  58. Kantarjian HM, Giles FJ, Greenberg PL, et al. Phase 2 study of romiplostim in patients with low- or intermediate-risk myelodysplastic syndrome receiving azacitidine therapy. Blood. 2010; 116(17): 3163–3170.
  59. Greenberg PL, Garcia-Manero G, Moore M, et al. Phase 2 study of romiplostim in patients with low- or intermediate-risk myelodysplastic syndrome receiving azacitidine therapy. Blood. 2010; 116(17): 3163–3170.
  60. Girmenia C, Candoni A, Delia M, et al. Infection control in patients with myelodysplastic syndromes who are candidates for active treatment: Expert panel consensus-based recommendations. Blood Rev. 2019; 34: 16–25.
  61. Nachtkamp K, Stark R, Strupp C, et al. Causes of death in 2877 patients with myelodysplastic syndromes. Ann Hematol. 2016; 95(6): 937–944.
  62. Greenberg PL, Stone RM, Al-Kali A, et al. Myelodysplastic syndromes, version 2.2017, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2017; 15(1): 60–87.
  63. Biesma DH, van den Tweel JG, Verdonck LF. Immunosuppressive therapy for hypoplastic myelodysplastic syndrome. Cancer. 1997; 79(8): 1548–1551, doi: 10.1002/(sici)1097-0142(19970415)79:8<1548::aid-cncr16>3.0.co;2-y.
  64. Saunthararajah Y, Nakamura R, Wesley R, et al. A simple method to predict response to immunosuppressive therapy in patients with myelodysplastic syndrome. Blood. 2003; 102(8): 3025–3027.
  65. Haider M, Al Ali N, Padron E, et al. Immunosuppressive therapy: exploring an underutilized treatment option for myelodysplastic syndrome. Clin Lymphoma Myeloma Leuk. 2016; 16 Suppl: S44–S48.
  66. Passweg JR, Giagounidis AAN, Simcock M, et al. Immunosuppressive therapy for patients with myelodysplastic syndrome: a prospective randomized multicenter phase III trial comparing antithymocyte globulin plus cyclosporine with best supportive care--SAKK 33/99. J Clin Oncol. 2011; 29(3): 303–309.
  67. Sloand EM, Wu CO, Greenberg P, et al. Factors affecting response and survival in patients with myelodysplasia treated with immunosuppressive therapy. J Clin Oncol. 2008; 26(15): 2505–2511.
  68. Stahl M, DeVeaux M, de Witte T, et al. The use of immunosuppressive therapy in MDS: clinical outcomes and their predictors in a large international patient cohort. Blood Adv. 2018; 2(14): 1765–1772.
  69. Shenoy N, Vallumsetla N, Rachmilewitz E, et al. Impact of iron overload and potential benefit from iron chelation in low-risk myelodysplastic syndrome. Blood. 2014; 124(6): 873–881.
  70. Zeidan AM, Griffiths EA. To chelate or not to chelate in MDS: that is the question! Blood Rev. 2018; 32(5): 368–377.
  71. Malcovati L, Germing U, Kuendgen A, et al. Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes. J Clin Oncol. 2007; 25(23): 3503–3510.
  72. Jin X, He X, Cao X, et al. Iron overload impairs normal hematopoietic stem and progenitor cells through reactive oxygen species and shortens survival in myelodysplastic syndrome mice. Haematologica. 2018; 103(10): 1627–1634.
  73. Chacko J, Pennell DJ, Tanner MA, et al. Myocardial iron loading by magnetic resonance imaging T2* in good prognostic myelodysplastic syndrome patients on long-term blood transfusions. Br J Haematol. 2007; 138(5): 587–593.
  74. Jensen PD, Jensen FT, Christensen T, et al. Relationship between hepatocellular injury and transfusional iron overload prior to and during iron chelation with desferrioxamine: a study in adult patients with acquired anemias. Blood. 2003; 101(1): 91–96.
  75. Gattermann N, Finelli C, Della Porta M, et al. Hematologic responses to deferasirox therapy in transfusion-dependent patients with myelodysplastic syndromes. Haematologica. 2012; 97(9): 1364–1371.
  76. Jensen PD, Heickendorff L, Pedersen B, et al. The effect of iron chelation on haemopoiesis in MDS patients with transfusional iron overload. Br J Haematol. 1996; 94(2): 288–299.
  77. Improta S, Villa MR, Volpe A, et al. Transfusion-dependent low-risk myelodysplastic patients receiving deferasirox: Long-term follow-up. Oncol Lett. 2013; 6(6): 1774–1778.
  78. Leitch HA, Parmar A, Wells RA, et al. Overall survival in lower IPSS risk MDS by receipt of iron chelation therapy, adjusting for patient-related factors and measuring from time of first red blood cell transfusion dependence: an MDS-CAN analysis. Br J Haematol. 2017 Oct. ; 179(1): 83–97.
  79. Remacha ÁF, Arrizabalaga B, Villegas A, et al. IRON-2 Study Group. Evolution of iron overload in patients with low-risk myelodysplastic syndrome: iron chelation therapy and organ complications. Ann Hematol. 2015; 94(5): 779–787.
  80. Rose C, Brechignac S, Vassilief D, et al. GFM (Groupe Francophone des Myélodysplasies). Does iron chelation therapy improve survival in regularly transfused lower risk MDS patients? A multicenter study by the GFM (Groupe Francophone des Myélodysplasies). Leuk Res. 2010; 34(7): 864–870.
  81. Mainous AG, Tanner RJ, Hulihan MM, et al. The impact of chelation therapy on survival in transfusional iron overload: a meta-analysis of myelodysplastic syndrome. Br J Haematol. 2014; 167(5): 720–723.
  82. Angelucci E, Li J, Greenberg P, et al. TELESTO Study Investigators. Iron chelation in transfusion-dependent patients with low- to intermediate-1-risk myelodysplastic syndromes: a randomized trial. Ann Intern Med. 2020; 172(8): 513–522.
  83. Komrokji R, Garcia-Manero G, Ades L, et al. Sotatercept with long-term extension for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes: a phase 2, dose-ranging trial. Lancet Haematol. 2018; 5(2): e63–e72.
  84. Steensma DP, Fenaux P, Van Eygen K, et al. Imetelstat achieves meaningful and durable transfusion independence in high transfusion-burden patients with lower-risk myelodysplastic syndromes in a phase II study. J Clin Oncol. 2021; 39(1): 48–56.
  85. Garcia-Manero G, Gore SD, Kambhampati S, et al. Efficacy and safety of extended dosing schedules of CC-486 (oral azacitidine) in patients with lower-risk myelodysplastic syndromes. Leukemia. 2016; 30(4): 889–896.
  86. Garcia-Manero G, Scott BL, Cogle CR, et al. CC-486 (oral azacitidine) in patients with myelodysplastic syndromes with pretreatment thrombocytopenia. Leuk Res. 2018; 72: 79–85.
  87. Garcia-Manero G, McCloskey J, Griffiths E, et al. Pharmacokinetic exposure equivalence and preliminary efficacy and safety from a randomized cross over phase 3 study (ASCERTAIN study) of an oral hypomethylating agent ASTX727 (cedazuridine/decitabine) compared to IV decitabine. Blood. 2019; 134(Suppl_1): 846–846.



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