Palabras clave
Síndromes mielodisplásicos, tratamiento hipometilante, experiencia latinoamericana y ensayos clínicos
Cómo citar
Iastrebner, M. (2019). Tratamiento hipometilante de los síndromes mielodisplásicos. Pasado, presente y futuro… (Partes 1 y 2). Revista Hematología, 23(1), 38–48. Recuperado a partir de https://www.revistahematologia.com.ar/index.php/Revista/article/view/87
Resumen
En un artículo(1) sobre terapia epigenética publicado hace poco más de 10 años, decíamos: “... el desarrollo de nuevos tratamientos altamente eficaces que presentan menores efectos secundarios para el paciente plantea un quiebre respecto a la terapéutica oncológica tradicional. Por un lado, ofrecen una expectativa mayor de supervivencia y una mejor calidad de vida, y por el otro, alcanzan a un número extenso de enfermos...”. Después de tanto tiempo transcurrido, cabe preguntarse si dichas expectativas se han hecho realidad. Los agentes hipometilantes (HMAs) han significado sin duda un avance terapéutico en la práctica diaria, pero su efectividad real no ha sido tan contundente como la esperada. Por lo tanto, esta terapéutica ha dejado abierta una amplia brecha entre las necesidades de muchos pacientes y los alcances reales de la misma. En este escenario de controversias se han desarrollado una serie de investigaciones prometedoras que podrían modificar el panorama a corto o mediano plazo. En el presente trabajo se analizarán los logros y las limitaciones del tratamiento hipometilante, procurando delinear futuras posibilidades terapéuticas. Este artículo constará de cuatro partes que tendrán como objetivo responder: ¿qué hemos aprendido en estos últimos 10 años de la experiencia internacional? (parte 1), ¿cómo fue la experiencia local en La-tinoamérica? (parte 2), ¿cuáles son los sistemas de estratificación recientemente validados que predicen resultados en el período post-falla al hipometilante? (parte 3) y ¿qué tratamiento debería utilizarse luego del fracaso al hipometilante? (parte 4).
Citas
1. Iastrebner M y col. Tratamiento Hipometilante de los Síndromes Mielodisplásicos. De la fisiopatogenia y la farmacología a la práctica clínica. Hematología. 2009; 13(1):16-28.
2. Sekeres MA et al. Characteristics of US patients with myelodysplastic syndromes: results of six cross-sectional physician surveys. J Natl Cancer Inst. 2008 Nov 5;100(21):1542-1551.
3. Sekeres MA. The epidemiology of myelodysplastic syndromes. Hematol Oncol Clin North Am. 2010 Apr;24(2):287-294.
4. Sekeres MA et al. Optimizing the use of hypomethylating agents in MDS: Selecting the candidate, predicting the response and enhancing the activity. Optimizing HMAs in MDS. Seminars in Hematology. 2017 S0037-1963(17)30056-2.
5. Fenaux P, Ades L. How we treat lower-risk myelodysplastic syndromes. Blood. 2013, May23;121(21):4280-4286.
6. Cheson BD et al. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006 Jul15;108(2):419-425.
7. Silverman LR et al. Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B. J Clin Oncol. 2006 Aug 20;24(24):3895-3903.
8. Kelaidi C et al. Long-term outcome of anemic lowerrisk myelodysplastic syndromes without 5q deletion refractory to or relapsing after erythropoiesis-stimulating agents. Leukemia. 2013 Jun;27(6):1283-1290.
9. Park S et al. Outcome of Lower-Risk Patients with Myelodysplastic Syndromes Without 5q Deletion After Failure of Erythropoiesis-Stimulating Agents. J Clin Oncol. 2017 May 10;35(14):1591-1597.
10.Thepot S et al. A randomized phase II trial of azacitidine +/- epoetin-beta in lower-risk myelodysplastic syndromes resistant to erythropoietic stimulating agents. Haematologica. 2016 Aug;101(8):918-925.
11. List A et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. NEJM. 2006 Oct 5;355(14):1456-1465.
12. Komrokji RS et al. Azacitidine Treatment for Lenalidomide (LEN)-Resistant Myelodysplastic Syndrome
(MDS) with Del 5q. Blood. 2012;120:3833.
13. Prebet T et al. Outcome of Patients Treated for Myelodysplastic Syndromes after Failure of Lenalidomide
Therapy. Blood. 2015;126(23), 95.
14. Komrokji RS et al. Optimal Treatment Order of Lenalidomide and Hypomethylating Agents for Lower- Risk Myelodysplastic Syndromes: A Report on Behalf of the MDS Clinical Research Consortium. Blood. 2016;128(22), 4322.
15. Kantarjian H et al. The incidence and impact of thrombocytopenia in myelodysplastic syndromes. Cancer. 2007 May 1;109(9):1705-1714.
16. Giagounidis A et al. Results of a randomized, double- blind study of romiplostim versus placebo in patients with low/intermediate-1-risk myelodysplastic syndrome and thrombocytopenia. Cancer. 2014 Jun 15;120(12):1838-1846.
17. Santini V. Treatment of low-risk myelodysplastic syndromes. Hematology ASH Educactional Program. 2016 Dec 2;2016(1):462-469.
18. Nomdedeu M et al. Excess mortality in the myelodysplastic syndromes. Am J Hematol. 2017 Feb;92(2):149-154.
19. Short N et al. Low-Dose Hypomethylating Agents Are Effective in Patients with Low- or Intermediate- 1-Risk Myelodysplastic Syndrome: A Report on Behalf of the MDS Clinical Research Consortium. Blood. 2015;126(23):94.
20. Jabbour EJ et al. A Randomized Phase II Study of Low-Dose Decitabine Versus Azacitidine in Patients with Low- or Intermediate-1-Risk Myelodysplastic Syndromes: A Report on Behalf of the MDS Clinical Research Consortium. Blood. 2016; 128:226.
21. Greenberg P et al. International scoring system for evaluating prognosis in myelodysplastic syndromes.
Blood. 1997 Mar;89(6):2079-2088.
22. Greenberg PL et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012 Sep;120(12):2454-2465.
23. Sekeres MA, Cutler C. How we treat higher-risk myelodysplastic syndromes. Blood. 2014 Feb;123(6):829-836.
24. Fenaux P et al. 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 Mar;10(3):223-232.
25. Lubbert M et al. Low-dose decitabine versus best supportive care in elderly patients with intermediateor high-risk myelodysplastic syndrome (MDS) ineligible for intensive chemotherapy: final results of the randomized phase III study of the European Organization
for Research and Treatment of Cancer Leukemia Group and the German MDS Study Group. J Clin Oncol. 2011 May;29(15):1987-1996.
26. Prebet T et al. Outcome of high-risk myelodysplastic syndrome after azacitidine treatment failure. J Clin Oncol. 2011 Aug;29(24):3322-3327.
27. Jabbour E et al. Outcome of patients with myelodysplastic syndrome after failure of decitabine therapy. Cancer. 2010 Aug;116(16):3830-3834.
28. Makishima H et al. Dynamics of clonal evolution in myelodysplastic syndromes. Nat Genet. 2017 Feb;49(2):204.
29. Craddock C et al. Azacitidine fails to eradicate leukemic stem/progenitor cell populations in patients with acute myeloid leukemia and myelodysplasia. Leukemia. 2013 Apr;27(5):1028.
30. Carraway HE. Treatment options for patients with myelodysplastic syndromes after hypomethylating agent failure. Hematology ASH Educational Program. 2016 Dec;2016(1):470-477.
31. DeZern AE et al. Differential response to hypomethylating agents based on sex: a report on behalf of the MDS Clinical Research Consortium (MDS CRC). Leuk Lymphoma. 2016,Oct24:1-7.
32. Duchmann M, Itzykson R. Choosing a hypomethylating agent in MDS: does gender matter? Leuk Lymphoma. 2017 Jun;58(6):1277-1278.
33. Traina F et al. Impact of molecular mutations on treatment response to DNMT inhibitors in myelodysplasia and related neoplasms. Leukemia. 2014 Jan;28(1):78-87.
34. Itzykson R et al. Impact of TET2 mutations on response rate to azacitidine in myelodysplastic syndromes and low blast count acute myeloid leukemias. Leukemia. 2011 Jul;25(7):1147-1152.
35. Bejar R et al. TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients. Blood. 2014 Oct 23;124(17):2705.
36. Apuri S et al. Evidence for Selective Benefit of Sequential Treatment with Hypomethylating Agents in Patients with Myelodysplastic Syndrome. Clin Lymphoma Myeloma. Leuk. 2017 Apr;17(4):211-214.
37. Ball B et al. Hypomethylating agent combination strategies in myelodysplastic syndromes: hopes and shortcomings. Leuk Lymphoma. 2017 May;58(5):1022-1036.
38. List AF et al. Extended survival and reduced risk of AML progression in erythroid-responsive lenalidomide- treated patients with lower-risk del(5q) MDS. Leukemia. 2014;May;28(5):1033-1040.
39. Sekeres MA et al. Phase 2 study of the lenalidomide and azacitidine combination in patients with higher- risk myelodysplastic syndromes. Blood. 2012 Dec 13;120(25):4945-4951.
40. Kenealy M et al. The addition of Lenalidomide to Azacytidine achieves higher responses but no improvement in twelve-month clinical benefit or PFS; main analysis Australian ALLG MDS Trial. Leukemia Research. April 2015; Volume 39, Supplement 1, Page S5.
41. Tobiasson M 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; Mar 7;4:e189.
42. Greenberg PL et al. A randomized controlled trial of romiplostim in patients with low- or intermediate- risk myelodysplastic syndrome receiving decitabine. Leuk Lymphoma. 2013; Feb;54(2):321-328.
43. Kantarjian HM et al. Phase 2 study of romiplostim in patients with low- or intermediate-risk myelodysplastic syndrome receiving azacitidine therapy. Blood. 2010; Oct 28;116(17):3163.
44. Dickinson MJ et al. Thrombopoietin (TPO) Receptor Agonist Eltrombopag in Combination with Azacitidine (AZA) for Primary Treatment of Myelodysplastic Syndromes (MDS) Patients with Thrombocytopenia: Outcomes from the Randomized, Placebo- Controlled, Phase III Support Study. Blood. 2018 Dec 20;132(25):2629-2638.
45. Cameron EE. Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nat Genet. 1999 Jan;21(1):103-107.
46. Eberharter A et al. Histone acetylation: a switch between repressive and permissive chromatin. Second in review series on chromatin dynamics. EMBO Rep. 2002 Mar;3(3):224-229.
47. Carew JS et al. Histone deacetylase inhibitors: mechanisms of cell death and promise in combination cancer therapy. Cancer Lett. 2008 Sep 28;269(1):7-17.
48. Issa JP et al. Results of phase 2 randomized study of low-dose decitabine with or without valproic acid in patients with myelodysplastic syndrome and acute myelogenous leukemia. Cancer. 2015 Feb 15;121(4):556-561.
49. Sekeres MA et al. Additional Analyses of a Randomized Phase II Study of Azacitidine Combined with Lenalidomide or with Vorinostat Vs. Azacitidine Monotherapy in Higher-Risk Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML): North American Intergroup Study SWOG
S1117. Blood. 2015; 126:908.
50. Garcia-Manero G et al. Panobinostat Plus Azacitidine in Adult Patients with MDS, CMML, or AML: Results of a Phase 2b Study. Blood. 2015; 126:2861.
51. Garcia-Manero G et al. A Randomized, Placebo- Controlled, Phase II Study of Pracinostat in Combination with Azacitidine (AZA) in Patients with Previously Untreated Myelodysplastic Syndrome (MDS). Blood. 2015; 126:911.
52. Prebet T et al. Prolonged administration of azacitidine with or without entinostat for myelodysplastic syndrome and acute myeloid leukemia with myelodysplasia-related changes: results of the US Leukemia Intergroup trial E1905. JCO. 2014 Apr 20;32(12):1242-1248.
53. Prebet T et al. Azacitidine with or without Entinostat for the treatment of therapy-related myeloid neoplasm: further results of the E1905 North American Leukemia Intergroup study. Br J Haematol. 2016 Feb;172(3):384-391.
54. Sekeres MA, Othus M, List AF, Odenike O, Stone RM, Gore SD et al. Randomized Phase II Study of Azacitidine Alone or in Combination With Lenalidomide or With Vorinostat in Higher-Risk Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia: North American Intergroup Study SWOG S1117. J Clin Oncol. 2017 Aug 20;35(24):2745-2753.
55. Yang H Et al. Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents. Leukemia.
2014 Jun;28(6):1280-1288.
56. Orskov AD et al. Hypomethylation and up-regulation of PD-1 in T cells by azacytidine in MDS/ AML patients: A rationale for combined targeting of PD-1 and DNA methylation. Oncotarget. 2015 Apr 20;6(11):9612-26.
57. Garcia-Manero G et al. Pembrolizumab, a PD-1 Inhibitor, in Patients with Myelodysplastic Syndrome after Failure of Hypomethylating Agent Treatment. Blood. 2016;128(22),345.
58. Garcia-Manero G et al. A Phase II Study Evaluating the Combination of Nivolumab or Ipilimumab with Azacitidine in Pts with Previously Treated or Untreated Myelodysplastic Syndromes (MDS). Blood. 2016;128(22),344.
59. Garcia-Manero G et al. Successful Emulation of IV Decitabine Pharmacokinetics with an Oral Fixed-Dose Combination of the Oral Cytidine Deaminase Inhibitor (CDAi) E7727 with Oral Decitabine, in Subjects with Myelodysplastic Syndromes: Final Data of
Phase 1 Study. Blood. 2016;128:114.
60. Fenaux P et al. 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; 10:223.
61. Kantarjian H et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer. 2006; 106:1794-803.
62. Arbelbide Jorge y col. Subcomisión de Síndromes Mielodisplásicos. Cumpliendo una década de trabajo cooperativo. Congreso de SAH Mar del Plata-2017.
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64. Lazzarino C y col. Factores de Riesgo clínico que influyen para alcanzar un tratamiento óptimo en SMD y LMMC. MDS-Foundation-Symposium, Valencia- 2017.
65. Iastrebner M y col. High Risk patients under HMAs. MDS-Foundation-Symposium, Valencia-2017.
66. Iastrebner M y col. Predictive factors of overall survival and treatment response in high-risk older patients with MDS and CMML under HMAs agents. EHA-Stockholm-2018.
67. Lazzarino C y col. Severe thrombocytopenia as a predictor of survival and response to hypomethylating agents: a sub-analysis of Latin-American cohort. EHA-Stockholm-2018.
68. Valeria Santini V. Novel therapeutic strategies: hypomethylating agents and beyond. Am Soc Hematol Educ Program. 2012;2012:65-73.
69. Dickinson M et al. Azacitidine with or without eltrombopag for first-line treatment of intermediate- or high-risk MDS with thrombocytopenia. Blood. 2018 Dec 20; 132(25): 2629-2638.
70. Oliva EN et al. Eltrombopag versus placebo for lowrisk myelodysplastic syndromes with thrombo cytopenia (EQoL-MDS): phase 1 results of a single- blind, randomised, controlled, phase 2 superiority trial. Lancet Haematol. 2017 Mar;4(3):e127-e136.
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77. Graef T et al. Successful treatment of relapsed AML after allogeneic stem cell transplantation with azacitidine. Leuk Res. 2007;31(2):257-259.
78. Jabbour E et al. Low-dose azacitidine after allogeneic stem cell transplantation for acute leukemia. Cancer. 2009;115(9):1899-1905.
79. Schroeder T et al. Treatment of acute myeloid leukemia or myelodysplastic syndrome relapse after allogeneic stem cell transplantation with azacitidine and donor lymphocyte infusions--a retrospective multicenter analysis from the German Cooperative Transplant Study Group. Biol Blood Marrow Transplant. 2015;21(4):653-660.
80. Oliva EN 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: e127-36.
2. Sekeres MA et al. Characteristics of US patients with myelodysplastic syndromes: results of six cross-sectional physician surveys. J Natl Cancer Inst. 2008 Nov 5;100(21):1542-1551.
3. Sekeres MA. The epidemiology of myelodysplastic syndromes. Hematol Oncol Clin North Am. 2010 Apr;24(2):287-294.
4. Sekeres MA et al. Optimizing the use of hypomethylating agents in MDS: Selecting the candidate, predicting the response and enhancing the activity. Optimizing HMAs in MDS. Seminars in Hematology. 2017 S0037-1963(17)30056-2.
5. Fenaux P, Ades L. How we treat lower-risk myelodysplastic syndromes. Blood. 2013, May23;121(21):4280-4286.
6. Cheson BD et al. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006 Jul15;108(2):419-425.
7. Silverman LR et al. Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B. J Clin Oncol. 2006 Aug 20;24(24):3895-3903.
8. Kelaidi C et al. Long-term outcome of anemic lowerrisk myelodysplastic syndromes without 5q deletion refractory to or relapsing after erythropoiesis-stimulating agents. Leukemia. 2013 Jun;27(6):1283-1290.
9. Park S et al. Outcome of Lower-Risk Patients with Myelodysplastic Syndromes Without 5q Deletion After Failure of Erythropoiesis-Stimulating Agents. J Clin Oncol. 2017 May 10;35(14):1591-1597.
10.Thepot S et al. A randomized phase II trial of azacitidine +/- epoetin-beta in lower-risk myelodysplastic syndromes resistant to erythropoietic stimulating agents. Haematologica. 2016 Aug;101(8):918-925.
11. List A et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. NEJM. 2006 Oct 5;355(14):1456-1465.
12. Komrokji RS et al. Azacitidine Treatment for Lenalidomide (LEN)-Resistant Myelodysplastic Syndrome
(MDS) with Del 5q. Blood. 2012;120:3833.
13. Prebet T et al. Outcome of Patients Treated for Myelodysplastic Syndromes after Failure of Lenalidomide
Therapy. Blood. 2015;126(23), 95.
14. Komrokji RS et al. Optimal Treatment Order of Lenalidomide and Hypomethylating Agents for Lower- Risk Myelodysplastic Syndromes: A Report on Behalf of the MDS Clinical Research Consortium. Blood. 2016;128(22), 4322.
15. Kantarjian H et al. The incidence and impact of thrombocytopenia in myelodysplastic syndromes. Cancer. 2007 May 1;109(9):1705-1714.
16. Giagounidis A et al. Results of a randomized, double- blind study of romiplostim versus placebo in patients with low/intermediate-1-risk myelodysplastic syndrome and thrombocytopenia. Cancer. 2014 Jun 15;120(12):1838-1846.
17. Santini V. Treatment of low-risk myelodysplastic syndromes. Hematology ASH Educactional Program. 2016 Dec 2;2016(1):462-469.
18. Nomdedeu M et al. Excess mortality in the myelodysplastic syndromes. Am J Hematol. 2017 Feb;92(2):149-154.
19. Short N et al. Low-Dose Hypomethylating Agents Are Effective in Patients with Low- or Intermediate- 1-Risk Myelodysplastic Syndrome: A Report on Behalf of the MDS Clinical Research Consortium. Blood. 2015;126(23):94.
20. Jabbour EJ et al. A Randomized Phase II Study of Low-Dose Decitabine Versus Azacitidine in Patients with Low- or Intermediate-1-Risk Myelodysplastic Syndromes: A Report on Behalf of the MDS Clinical Research Consortium. Blood. 2016; 128:226.
21. Greenberg P et al. International scoring system for evaluating prognosis in myelodysplastic syndromes.
Blood. 1997 Mar;89(6):2079-2088.
22. Greenberg PL et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012 Sep;120(12):2454-2465.
23. Sekeres MA, Cutler C. How we treat higher-risk myelodysplastic syndromes. Blood. 2014 Feb;123(6):829-836.
24. Fenaux P et al. 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 Mar;10(3):223-232.
25. Lubbert M et al. Low-dose decitabine versus best supportive care in elderly patients with intermediateor high-risk myelodysplastic syndrome (MDS) ineligible for intensive chemotherapy: final results of the randomized phase III study of the European Organization
for Research and Treatment of Cancer Leukemia Group and the German MDS Study Group. J Clin Oncol. 2011 May;29(15):1987-1996.
26. Prebet T et al. Outcome of high-risk myelodysplastic syndrome after azacitidine treatment failure. J Clin Oncol. 2011 Aug;29(24):3322-3327.
27. Jabbour E et al. Outcome of patients with myelodysplastic syndrome after failure of decitabine therapy. Cancer. 2010 Aug;116(16):3830-3834.
28. Makishima H et al. Dynamics of clonal evolution in myelodysplastic syndromes. Nat Genet. 2017 Feb;49(2):204.
29. Craddock C et al. Azacitidine fails to eradicate leukemic stem/progenitor cell populations in patients with acute myeloid leukemia and myelodysplasia. Leukemia. 2013 Apr;27(5):1028.
30. Carraway HE. Treatment options for patients with myelodysplastic syndromes after hypomethylating agent failure. Hematology ASH Educational Program. 2016 Dec;2016(1):470-477.
31. DeZern AE et al. Differential response to hypomethylating agents based on sex: a report on behalf of the MDS Clinical Research Consortium (MDS CRC). Leuk Lymphoma. 2016,Oct24:1-7.
32. Duchmann M, Itzykson R. Choosing a hypomethylating agent in MDS: does gender matter? Leuk Lymphoma. 2017 Jun;58(6):1277-1278.
33. Traina F et al. Impact of molecular mutations on treatment response to DNMT inhibitors in myelodysplasia and related neoplasms. Leukemia. 2014 Jan;28(1):78-87.
34. Itzykson R et al. Impact of TET2 mutations on response rate to azacitidine in myelodysplastic syndromes and low blast count acute myeloid leukemias. Leukemia. 2011 Jul;25(7):1147-1152.
35. Bejar R et al. TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients. Blood. 2014 Oct 23;124(17):2705.
36. Apuri S et al. Evidence for Selective Benefit of Sequential Treatment with Hypomethylating Agents in Patients with Myelodysplastic Syndrome. Clin Lymphoma Myeloma. Leuk. 2017 Apr;17(4):211-214.
37. Ball B et al. Hypomethylating agent combination strategies in myelodysplastic syndromes: hopes and shortcomings. Leuk Lymphoma. 2017 May;58(5):1022-1036.
38. List AF et al. Extended survival and reduced risk of AML progression in erythroid-responsive lenalidomide- treated patients with lower-risk del(5q) MDS. Leukemia. 2014;May;28(5):1033-1040.
39. Sekeres MA et al. Phase 2 study of the lenalidomide and azacitidine combination in patients with higher- risk myelodysplastic syndromes. Blood. 2012 Dec 13;120(25):4945-4951.
40. Kenealy M et al. The addition of Lenalidomide to Azacytidine achieves higher responses but no improvement in twelve-month clinical benefit or PFS; main analysis Australian ALLG MDS Trial. Leukemia Research. April 2015; Volume 39, Supplement 1, Page S5.
41. Tobiasson M 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; Mar 7;4:e189.
42. Greenberg PL et al. A randomized controlled trial of romiplostim in patients with low- or intermediate- risk myelodysplastic syndrome receiving decitabine. Leuk Lymphoma. 2013; Feb;54(2):321-328.
43. Kantarjian HM et al. Phase 2 study of romiplostim in patients with low- or intermediate-risk myelodysplastic syndrome receiving azacitidine therapy. Blood. 2010; Oct 28;116(17):3163.
44. Dickinson MJ et al. Thrombopoietin (TPO) Receptor Agonist Eltrombopag in Combination with Azacitidine (AZA) for Primary Treatment of Myelodysplastic Syndromes (MDS) Patients with Thrombocytopenia: Outcomes from the Randomized, Placebo- Controlled, Phase III Support Study. Blood. 2018 Dec 20;132(25):2629-2638.
45. Cameron EE. Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nat Genet. 1999 Jan;21(1):103-107.
46. Eberharter A et al. Histone acetylation: a switch between repressive and permissive chromatin. Second in review series on chromatin dynamics. EMBO Rep. 2002 Mar;3(3):224-229.
47. Carew JS et al. Histone deacetylase inhibitors: mechanisms of cell death and promise in combination cancer therapy. Cancer Lett. 2008 Sep 28;269(1):7-17.
48. Issa JP et al. Results of phase 2 randomized study of low-dose decitabine with or without valproic acid in patients with myelodysplastic syndrome and acute myelogenous leukemia. Cancer. 2015 Feb 15;121(4):556-561.
49. Sekeres MA et al. Additional Analyses of a Randomized Phase II Study of Azacitidine Combined with Lenalidomide or with Vorinostat Vs. Azacitidine Monotherapy in Higher-Risk Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML): North American Intergroup Study SWOG
S1117. Blood. 2015; 126:908.
50. Garcia-Manero G et al. Panobinostat Plus Azacitidine in Adult Patients with MDS, CMML, or AML: Results of a Phase 2b Study. Blood. 2015; 126:2861.
51. Garcia-Manero G et al. A Randomized, Placebo- Controlled, Phase II Study of Pracinostat in Combination with Azacitidine (AZA) in Patients with Previously Untreated Myelodysplastic Syndrome (MDS). Blood. 2015; 126:911.
52. Prebet T et al. Prolonged administration of azacitidine with or without entinostat for myelodysplastic syndrome and acute myeloid leukemia with myelodysplasia-related changes: results of the US Leukemia Intergroup trial E1905. JCO. 2014 Apr 20;32(12):1242-1248.
53. Prebet T et al. Azacitidine with or without Entinostat for the treatment of therapy-related myeloid neoplasm: further results of the E1905 North American Leukemia Intergroup study. Br J Haematol. 2016 Feb;172(3):384-391.
54. Sekeres MA, Othus M, List AF, Odenike O, Stone RM, Gore SD et al. Randomized Phase II Study of Azacitidine Alone or in Combination With Lenalidomide or With Vorinostat in Higher-Risk Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia: North American Intergroup Study SWOG S1117. J Clin Oncol. 2017 Aug 20;35(24):2745-2753.
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