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Lenalidomide for the Treatment of MDS

  • Aristoteles Giagounidis
  • Lionel Adès
Chapter
Part of the Hematologic Malignancies book series (HEMATOLOGIC)

Abstract

Myelodysplastic syndromes (MDS) constitute a heterogeneous group of clonal hematopoietic disorders characterized by bone marrow (BM) failure, dysplasia, and an increased risk of developing acute myeloid leukemia (AML) [1]. The most prevalent cytogenetic abnormality is a partial deletion of the long arm of chromosome 5, del(5q), which is present in about 15% of cases [2]. Anemia is the predominant cytopenia in the large majority of low-risk MDS cases, being the focus of most therapeutic interventions. It often requires repeated RBC transfusions, leading to potential iron overload.

Notes

Acknowledgment

This work was in part supported by the Deutsche José Carreras Leukämie-Stiftung.

References

  1. 1.
    Aul C, Bowen DT, Yoshida Y. Pathogenesis, etiology and epidemiology of myelodysplastic syndromes. Haematologica. 1998;83:71–86.PubMedGoogle Scholar
  2. 2.
    Schanz J, Steidl C, Fonatsch C, et al. Coalesced multicentric analysis of 2,351 patients with myelodysplastic syndromes indicates an underestimation of poor-risk cytogenetics of myelodysplastic syndromes in the international prognostic scoring system. J Clin Oncol. 2011;29:1963–70.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Passweg JR, Giagounidis AA, 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;29:303–9.CrossRefPubMedGoogle Scholar
  4. 4.
    Sloand EM, Olnes MJ, Shenoy A, et al. Alemtuzumab treatment of intermediate-1 myelodysplasia patients is associated with sustained improvement in blood counts and cytogenetic remissions. J Clin Oncol. 2010;28:5166–73.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    List A, Kurtin S, Roe DJ, et al. Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med. 2005;352:549–57.CrossRefPubMedGoogle Scholar
  6. 6.
    List A, Dewald G, Bennett J, et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med. 2006;355:1456–65.CrossRefPubMedGoogle Scholar
  7. 7.
    Fenaux P, Giagounidis A, Selleslag D, et al. A randomized phase 3 study of lenalidomide versus placebo in RBC transfusion-dependent patients with Low-/Intermediate-1-risk myelodysplastic syndromes with del5q. Blood. 2011;118:3765–76.CrossRefPubMedGoogle Scholar
  8. 8.
    Pellagatti A, Jadersten M, Forsblom AM, et al. Lenalidomide inhibits the malignant clone and up-regulates the SPARC gene mapping to the commonly deleted region in 5q- syndrome patients. Proc Natl Acad Sci U S A. 2007;104:11406–11.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    List A, Baker A, Green S, Bellamy W. Lenalidomide: targeted anemia therapy for myelodysplastic syndromes. Cancer Control. 2006;13:4–11.CrossRefPubMedGoogle Scholar
  10. 10.
    Tehranchi R, Woll PS, Anderson K, et al. Persistent malignant stem cells in del(5q) myelodysplasia in remission. N Engl J Med. 2010;363:1025–37.CrossRefPubMedGoogle Scholar
  11. 11.
    Gohring G, Giagounidis A, Busche G, et al. Cytogenetic follow-up by karyotyping and fluorescence in situ hybridization: implications for monitoring patients with myelodysplastic syndrome and deletion 5q treated with lenalidomide. Haematologica. 2011;96:319–22.CrossRefPubMedGoogle Scholar
  12. 12.
    Wei S, Chen X, McGraw K, et al. Lenalidomide promotes p53 degradation by inhibiting MDM2 auto-ubiquitination in myelodysplastic syndrome with chromosome 5q deletion. Oncogene. 2013;32:1110–20.CrossRefPubMedGoogle Scholar
  13. 13.
    Wei S, Chen X, Rocha K, et al. A critical role for phosphatase haplodeficiency in the selective suppression of deletion 5q MDS by lenalidomide. Proc Natl Acad Sci U S A. 2009;106:12974–9.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Ito T, Ando H, Suzuki T, et al. Identification of a primary target of thalidomide teratogenicity. Science. 2010;327:1345–50.CrossRefPubMedGoogle Scholar
  15. 15.
    Kronke J, Fink EC, Hollenbach PW, et al. Lenalidomide induces ubiquitination and degradation of CK1alpha in del(5q) MDS. Nature. 2015;523:183–8.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Boultwood J, Fidler C, Strickson AJ, et al. Narrowing and genomic annotation of the commonly deleted region of the 5q- syndrome. Blood. 2002;99:4638–41.CrossRefPubMedGoogle Scholar
  17. 17.
    Fink EC, Ebert BL. The novel mechanism of lenalidomide activity. Blood. 2015;126:2366–9.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Jadersten M, Saft L, Pellagatti A, et al. Clonal heterogeneity in the 5q- syndrome: p53 expressing progenitors prevail during lenalidomide treatment and expand at disease progression. Haematologica. 2009;94:1762–6.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Jadersten M, Saft L, Smith A, et al. TP53 mutations in low-risk myelodysplastic syndromes with del(5q) predict disease progression. J Clin Oncol. 2011;29:1971–9.CrossRefPubMedGoogle Scholar
  20. 20.
    Schuler E, Giagounidis A, Haase D, et al. Results of a multicenter prospective phase II trial investigating the safety and efficacy of lenalidomide in patients with myelodysplastic syndromes with isolated del(5q) (LE-MON 5). Leukemia. 2016;30:1580–2.CrossRefPubMedGoogle Scholar
  21. 21.
    Jadersten M, Karsan A. Clonal evolution in myelodysplastic syndromes with isolated del(5q): the importance of genetic monitoring. Haematologica. 2011;96:177–80.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Narla A, Dutt S, McAuley JR, et al. Dexamethasone and lenalidomide have distinct functional effects on erythropoiesis. Blood. 2011;118:2296–304.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Ximeri M, Galanopoulos A, Klaus M, et al. Effect of lenalidomide therapy on hematopoiesis of patients with myelodysplastic syndrome associated with chromosome 5q deletion. Haematologica. 2010;95:406–14.CrossRefPubMedGoogle Scholar
  24. 24.
    Sekeres MA, Maciejewski JP, Giagounidis AA, et al. Relationship of treatment-related cytopenias and response to lenalidomide in patients with lower-risk myelodysplastic syndromes. J Clin Oncol. 2008;26:5943–9.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Padron E, Komrokji R, List AF. Biology and treatment of the 5q- syndrome. Expert Rev Hematol. 2011;4:61–9.CrossRefPubMedGoogle Scholar
  26. 26.
    Gohring G, Giagounidis A, Busche G, et al. Patients with del(5q) MDS who fail to achieve sustained erythroid or cytogenetic remission after treatment with lenalidomide have an increased risk for clonal evolution and AML progression. Ann Hematol. 2010;89:365–74.CrossRefPubMedGoogle Scholar
  27. 27.
    Germing U, Lauseker M, Hildebrandt B, et al. Survival, prognostic factors and rates of leukemic transformation in 381 untreated patients with MDS and del(5q): a multicenter study. Leukemia. 2012;26:1286–92.CrossRefPubMedGoogle Scholar
  28. 28.
    Ades L, Le Bras F, Sebert M, et al. Treatment with lenalidomide does not appear to increase the risk of progression in lower risk myelodysplastic syndromes with 5q deletion. A comparative analysis by the Groupe Francophone des Myelodysplasies. Haematologica. 2012;97:213–8.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Kuendgen A, Lauseker M, List AF, et al. Lenalidomide does not increase AML progression risk in RBC transfusion-dependent patients with low- or intermediate-1-risk MDS with del(5q): a comparative analysis. Leukemia. 2013;27:1072–9.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    List AF, Bennett JM, Sekeres MA, et al. Extended survival and reduced risk of AML progression in erythroid-responsive lenalidomide-treated patients with lower-risk del(5q) MDS. Leukemia. 2015;29:2452.CrossRefPubMedGoogle Scholar
  31. 31.
    Ades L, Boehrer S, Prebet T, et al. Efficacy and safety of lenalidomide in intermediate-2 or high-risk myelodysplastic syndromes with 5q deletion: results of a phase 2 study. Blood. 2009;113:3947–52.CrossRefPubMedGoogle Scholar
  32. 32.
    Ades L, Prebet T, Stamatoullas A, et al. Lenalidomide combined with intensive chemotherapy in acute myeloid leukemia and higher-risk myelodysplastic syndrome with 5q deletion. Results of a phase II study by the Groupe Francophone Des Myelodysplasies. Haematologica. 2017;102:728–35.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Sekeres MA, Tiu RV, Komrokji R, et al. Phase 2 study of the lenalidomide and azacitidine combination in patients with higher-risk myelodysplastic syndromes. Blood. 2012;120:4945–51.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Raza A, Reeves JA, Feldman EJ, et al. Phase 2 study of lenalidomide in transfusion-dependent, low-risk, and intermediate-1 risk myelodysplastic syndromes with karyotypes other than deletion 5q. Blood. 2008;111:86–93.CrossRefPubMedGoogle Scholar
  35. 35.
    Ebert BL, Galili N, Tamayo P, et al. An erythroid differentiation signature predicts response to lenalidomide in myelodysplastic syndrome. PLoS Med. 2008;5:e35.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    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;34:2988–96.CrossRefPubMedGoogle Scholar
  37. 37.
    Toma A, Kosmider O, Chevret S, et al. Lenalidomide with or without erythropoietin in transfusion-dependent erythropoiesis-stimulating agent-refractory lower-risk MDS without 5q deletion. Leukemia. 2016;30:897–905.CrossRefPubMedGoogle Scholar
  38. 38.
    List AF, Sun Z, Verma A, et al. Combined treatment with lenalidomide (LEN) and epoetin alfa (EA) is superior to lenalidomide alone in patients with erythropoietin (Epo)-refractory, lower risk (LR) non-deletion 5q [Del(5q)] myelodysplastic syndrome (MDS): results of the E2905 intergroup study-an ECOG-ACRIN cancer research group study, grant CA180820, and the National Cancer Institute of the National Institutes of Health. Blood. 2016;128:223.Google Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Marien Hospital DüsseldorfKlinik für Onkologie, Hämatologie und PalliativmedizinDüsseldorfGermany
  2. 2.Hopital Saint Louis and Paris 7 UniversityParisFrance

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