Following in the footsteps of acute myeloid leukemia: are we witnessing the start of a therapeutic revolution for higher-risk myelodysplastic syndromes?

References

• 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.
   PubMed Web of Science ®Google Scholar
• Bewersdorf JP, Zeidan AM. Transforming growth factor (TGF)-beta pathway as a therapeutic target in lower risk myelodysplastic syndromes. Leukemia. 2019;33(6):1303–1312.
   PubMed Web of Science ®Google Scholar
• Zeidan AM, Shallis RM, Wang R, et al. Epidemiology of myelodysplastic syndromes: why characterizing the beast is a prerequisite to taming it. Blood Rev. 2019;34:1–15.
   PubMed Web of Science ®Google Scholar
• Rollison DE, Howlader N, Smith MT, et al. Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders in the United States, 2001–2004 using data from the NAACCR and SEER programs. Blood. 2008;112(1):45–52.
   PubMed Web of Science ®Google Scholar
• Fenaux P, Mufti GJ, Hellstrom-Lindberg E, 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(3):223–232.
   PubMed Web of Science ®Google Scholar
• Kantarjian H, Oki Y, Garcia-Manero G, et al. Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood. 2007;109(1):52–57.
   PubMed Web of Science ®Google Scholar
• Bewersdorf JP, Stahl M, Zeidan AM. Are we witnessing the start of a therapeutic revolution in acute myeloid leukemia? Leuk Lymphoma. 2019;60(6):1354–1369.
   PubMed Web of Science ®Google Scholar
• Chokr N, Pine AB, Bewersdorf JP, et al. Getting personal with myelodysplastic syndromes: is now the right time? Expert Rev Hematol. 2019;12(4):215–224.
   PubMed Web of Science ®Google Scholar
• Bejar R. Myelodysplastic syndromes diagnosis: what is the role of molecular testing? Curr Hematol Malig Rep. 2015;10(3):282–291.
   PubMed Web of Science ®Google Scholar
• Lee EJ, Podoltsev N, Gore SD, et al. The evolving field of prognostication and risk stratification in MDS: recent developments and future directions. Blood Rev. 2016;30(1):1–10.
   PubMed Web of Science ®Google Scholar
• Zeidan AM, Sekeres MA, Garcia-Manero G, et al. Comparison of risk stratification tools in predicting outcomes of patients with higher-risk myelodysplastic syndromes treated with azanucleosides. Leukemia. 2016;30(3):649–657.
   PubMed Web of Science ®Google Scholar
• Zeidan AM, Sekeres MA, Wang XF, et al. Comparing the prognostic value of risk stratifying models for patients with lower-risk myelodysplastic syndromes: is one model better? Am J Hematol. 2015;90(11):1036–1040.
   PubMed Web of Science ®Google Scholar
• Pfeilstöcker M, Tuechler H, Sanz G, et al. Time-dependent changes in mortality and transformation risk in MDS. Blood. 2016;128(7):902–910.
   PubMed Web of Science ®Google Scholar
• Greenberg PL, Tuechler H, Schanz J, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012;120(12):2454–2465.
   PubMed Web of Science ®Google Scholar
• Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89(6):2079–2088.
   PubMed Web of Science ®Google Scholar
• Benton CB, Khan M, Sallman D, et al. Prognosis of patients with intermediate risk IPSS-R myelodysplastic syndrome indicates variable outcomes and need for models beyond IPSS-R. Am J Hematol. 2018;93(10):1245–1253.
   PubMed Web of Science ®Google Scholar
• Bejar R. Clinical and genetic predictors of prognosis in myelodysplastic syndromes. Haematologica. 2014;99(6):956–964.
   PubMed Web of Science ®Google Scholar
• Network NCC. NCCN Guidelines Version 2.2019: myelodysplastic syndromes. Vol. 2018; 2019.
   Google Scholar
• de Witte T, Bowen D, Robin M, et al. Allogeneic hematopoietic stem cell transplantation for MDS and CMML: recommendations from an international expert panel. Blood. 2017;129(13):1753–1762.
   PubMed Web of Science ®Google Scholar
• Platzbecker U. Treatment of MDS. Blood. 2019;133(10):1096–1107.
   PubMed Web of Science ®Google Scholar
• Haferlach T, Nagata Y, Grossmann V, et al. Landscape of genetic lesions in 944 patients with myelodysplastic syndromes. Leukemia. 2014;28(2):241–247.
   PubMed Web of Science ®Google Scholar
• Bejar R, Papaemmanuil E, Haferlach T, et al. Somatic mutations in MDS patients are associated with clinical features and predict prognosis independent of the IPSS-R: analysis of combined datasets from the international working group for prognosis in MDS-molecular committee. Blood. 2015;126(23):907–907.
   Web of Science ®Google Scholar
• Steensma DP. How I use molecular genetic tests to evaluate patients who have or may have myelodysplastic syndromes. Blood. 2018;132(16):1657–1663.
   PubMed Web of Science ®Google Scholar
• Bejar R, Lord A, Stevenson K, et al. TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients. Blood. 2014;124(17):2705–2712.
   PubMed Web of Science ®Google Scholar
• Deeg HJ, Scott BL, Fang M, et al. Five-group cytogenetic risk classification, monosomal karyotype, and outcome after hematopoietic cell transplantation for MDS or acute leukemia evolving from MDS. Blood. 2012;120(7):1398–1408.
   PubMed Web of Science ®Google Scholar
• Sorror ML, Sandmaier BM, Storer BE, et al. Comorbidity and disease status based risk stratification of outcomes among patients with acute myeloid leukemia or myelodysplasia receiving allogeneic hematopoietic cell transplantation. J Clin Oncol. 2007;25(27):4246–4254.
   PubMed Web of Science ®Google Scholar
• Della Porta MG, Galli A, Bacigalupo A, et al. Clinical effects of driver somatic mutations on the outcomes of patients with myelodysplastic syndromes treated with allogeneic hematopoietic stem-cell transplantation. J Clin Oncol. 2016;34(30):3627–3637.
   PubMed Web of Science ®Google Scholar
• Bejar R, Stevenson KE, Caughey B, et al. Somatic mutations predict poor outcome in patients with myelodysplastic syndrome after hematopoietic stem-cell transplantation. J Clin Oncol. 2014;32(25):2691–2698.
   PubMed Web of Science ®Google Scholar
• Lindsley RC, Saber W, Mar BG, et al. Prognostic mutations in myelodysplastic syndrome after stem-cell transplantation. N Engl J Med. 2017;376(6):536–547.
   PubMed Web of Science ®Google Scholar
• Schetelig J, de Wreede LC, van Gelder M, et al. Late treatment-related mortality versus competing causes of death after allogeneic transplantation for myelodysplastic syndromes and secondary acute myeloid leukemia. Leukemia. 2019;33(3):686–695.
   PubMed Web of Science ®Google Scholar
• Bacigalupo A, Ballen K, Rizzo D, et al. Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transplant. 2009;15(12):1628–1633.
   PubMed Web of Science ®Google Scholar
• Jurado M, Deeg HJ, Storer B, et al. Hematopoietic stem cell transplantation for advanced myelodysplastic syndrome after conditioning with busulfan and fractionated total body irradiation is associated with low relapse rate but considerable nonrelapse mortality. Biol Blood Marrow Transplant. 2002;8(3):161–169.
   PubMed Web of Science ®Google Scholar
• Heidenreich S, Ziagkos D, de Wreede LC, et al. Allogeneic stem cell transplantation for patients age ≥ 70 years with myelodysplastic syndrome: a retrospective study of the MDS subcommittee of the chronic malignancies working party of the EBMT. Biol Blood Marrow Transplant. 2017;23(1):44–52.
   PubMed Web of Science ®Google Scholar
• Atallah E, Logan B, Chen M, et al. Comparison of patient age groups in transplantation for myelodysplastic syndrome: the medicare coverage with evidence development study. JAMA Oncol. 2020;6(4):486.
   PubMed Web of Science ®Google Scholar
• Prem S, Atenafu EG, Lam W, et al. Allogeneic stem cell transplant in myelodysplastic syndrome-factors impacting survival. Eur J Haematol. 2020;104(2):116–124.
   PubMed Web of Science ®Google Scholar
• Bewersdorf JP, Shallis RM, Boddu PC, et al. The minimal that kills: why defining and targeting measurable residual disease is the “Sine Qua Non” for further progress in management of acute myeloid leukemia. Blood Rev. 2019. DOI:10.1016/j.blre.2019.100650
   Web of Science ®Google Scholar
• Mo XD, Qin YZ, Zhang XH, et al. Minimal residual disease monitoring and preemptive immunotherapy in myelodysplastic syndrome after allogeneic hematopoietic stem cell transplantation. Ann Hematol. 2016;95(8):1233–1240.
   PubMed Web of Science ®Google Scholar
• Schuurhuis GJ, Heuser M, Freeman S, et al. Minimal/measurable residual disease in AML: a consensus document from the European LeukemiaNet MRD Working Party. Blood. 2018;131(12):1275–1291.
   PubMed Web of Science ®Google Scholar
• Walter RB, Gyurkocza B, Storer BE, et al. Comparison of minimal residual disease as outcome predictor for AML patients in first complete remission undergoing myeloablative or nonmyeloablative allogeneic hematopoietic cell transplantation. Leukemia. 2015;29(1):137–144.
   PubMed Web of Science ®Google Scholar
• Warlick ED, Cioc A, DeFor T, et al. Allogeneic stem cell transplantation for adults with myelodysplastic syndromes: importance of pretransplant disease burden. Biol Blood Marrow Transplant. 2009;15(1):30–38.
   PubMed Web of Science ®Google Scholar
• Mo X, Zhang X, Xu L, et al. Minimal residual disease-directed immunotherapy for high-risk myelodysplastic syndrome after allogeneic hematopoietic stem cell transplantation. Front Med. 2019;13(3):354–364.
   PubMed Web of Science ®Google Scholar
• Platzbecker U, Middeke JM, Sockel K, et al. Measurable residual disease-guided treatment with azacitidine to prevent haematological relapse in patients with myelodysplastic syndrome and acute myeloid leukaemia (RELAZA2): an open-label, multicentre, phase 2 trial. Lancet Oncol. 2018;19(12):1668–1679.
   PubMed Web of Science ®Google Scholar
• de Witte TM, Bowen D, Robin M, et al. Should patients with high-risk or transformed myelodysplastic syndrome proceed directly to allogeneic transplant without prior cytoreduction by remission-induction chemotherapy or hypomethylating agent therapy? Clin Lymphoma Myeloma Leuk. 2014;14(Suppl):S42–S45.
   PubMed Web of Science ®Google Scholar
• Ravandi F, Issa JP, Garcia-Manero G, et al. Superior outcome with hypomethylating therapy in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome and chromosome 5 and 7 abnormalities. Cancer. 2009;115(24):5746–5751.
   PubMed Web of Science ®Google Scholar
• Kantarjian H, Beran M, Cortes J, et al. Long-term follow-up results of the combination of topotecan and cytarabine and other intensive chemotherapy regimens in myelodysplastic syndrome. Cancer. 2006;106(5):1099–1109.
   PubMed Web of Science ®Google Scholar
• Beran M, Shen Y, Kantarjian H, et al. High-dose chemotherapy in high-risk myelodysplastic syndrome: covariate-adjusted comparison of five regimens. Cancer. 2001;92(8):1999–2015.
   PubMed Web of Science ®Google Scholar
• Strati P, Garcia-Manero G, Zhao C, et al. Intensive chemotherapy is more effective than hypomethylating agents for the treatment of younger patients with myelodysplastic syndrome and elevated bone marrow blasts. Am J Hematol. 2019;94(7):E188–E190.
   PubMed Web of Science ®Google Scholar
• Welch JS, Petti AA, Miller CA, et al. TP53 and decitabine in acute myeloid leukemia and myelodysplastic syndromes. N Engl J Med. 2016;375(21):2023–2036.
   PubMed Web of Science ®Google Scholar
• Lancet JE, Uy GL, Cortes JE, et al. CPX-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia. J Clin Oncol. 2018;36(26):2684–2692.
   PubMed Web of Science ®Google Scholar
• Kantarjian H, Issa JP, Rosenfeld CS, et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer. 2006;106(8):1794–1803.
   PubMed Web of Science ®Google Scholar
• Lubbert M, Suciu S, Baila L, et al. Low-dose decitabine versus best supportive care in elderly patients with intermediate- or high-risk myelodysplastic syndrome (MDS) ineligible for intensive chemotherapy: final results of the randomized phase III study of the European Organisation for Research and Treatment of Cancer Leukemia Group and the German MDS Study Group. J Clin Oncol. 2011;29(15):1987–1996.
   PubMed Web of Science ®Google Scholar
• Bernal T, Martinez-Camblor P, Sanchez-Garcia J, et al. Effectiveness of azacitidine in unselected high-risk myelodysplastic syndromes: results from the Spanish registry. Leukemia. 2015;29(9):1875–1881.
   PubMed Web of Science ®Google Scholar
• Zeidan AM, Stahl M, DeVeaux M, et al. Counseling patients with higher-risk MDS regarding survival with azacitidine therapy: are we using realistic estimates? Blood Cancer J. 2018;8(6):55
   PubMed Web of Science ®Google Scholar
• Zeidan A, Hu X, Zhu W, et al. Association of provider experience and clinical outcomes in patients with myelodysplastic syndromes receiving hypomethylating agents. Leuk Lymphoma. 2019;61(2):397–408.
   PubMed Web of Science ®Google Scholar
• Zeidan AM, Stahl M, Hu X, et al. Long-term survival of older patients with MDS treated with HMA therapy without subsequent stem cell transplantation. Blood. 2018;131(7):818–821.
   PubMed Web of Science ®Google Scholar
• Santini V. How I treat MDS after hypomethylating agent failure. Blood. 2019;133(6):521–529.
   PubMed Web of Science ®Google Scholar
• Muller-Thomas C, Schuster T, Peschel C, et al. A limited number of 5-azacitidine cycles can be effective treatment in MDS. Ann Hematol. 2009;88(3):213–219.
   PubMed Web of Science ®Google Scholar
• Silverman LR, Fenaux P, Mufti GJ, et al. Continued azacitidine therapy beyond time of first response improves quality of response in patients with higher-risk myelodysplastic syndromes. Cancer. 2011;117(12):2697–2702.
   PubMed Web of Science ®Google Scholar
• Voso MT, Breccia M, Lunghi M, et al. Rapid loss of response after withdrawal of treatment with azacitidine: a case series in patients with higher-risk myelodysplastic syndromes or chronic myelomonocytic leukemia. Eur J Haematol. 2013;90(4):345–348.
   PubMed Web of Science ®Google Scholar
• Jabbour EJ, Garcia-Manero G, Strati P, et al. Outcome of patients with low-risk and intermediate-1-risk myelodysplastic syndrome after hypomethylating agent failure: a report on behalf of the MDS Clinical Research Consortium. Cancer. 2015;121(6):876–882.
   PubMed Web of Science ®Google Scholar
• Prebet T, Gore SD, Esterni B, et al. Outcome of high-risk myelodysplastic syndrome after azacitidine treatment failure. J Clin Oncol. 2011;29(24):3322–3327.
   PubMed Web of Science ®Google Scholar
• Jabbour E, Garcia-Manero G, Batty N, et al. Outcome of patients with myelodysplastic syndrome after failure of decitabine therapy. Cancer. 2010;116(16):3830–3834.
   PubMed Web of Science ®Google Scholar
• O'Connell CL, Kropf PL, Punwani N, et al. Phase I results of a multicenter clinical trial combining guadecitabine, a DNA methyltransferase inhibitor, with atezolizumab, an immune checkpoint inhibitor, in patients with relapsed or refractory myelodysplastic syndrome or chronic myelomonocytic leukemia. Blood. 2018;132(Supplement 1):1811–1811.
   Google Scholar
• Garcia-Manero G, McCloskey J, Griffiths EA, 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(Supplement_1):846–846.
   PubMed Web of Science ®Google Scholar
• Assi R, Kantarjian HM, Daver NG, et al. Results of a Phase 2, open-label study of Idarubicin (I), Cytarabine (A) and Nivolumab (Nivo) in patients with newly diagnosed Acute Myeloid Leukemia (AML) and high-risk Myelodysplastic Syndrome (MDS). Blood. 2018;132(Supplement 1):905–905.
   Web of Science ®Google Scholar
• Sallman DA, Asch AS, Al Malki MM, et al. The first-in-class anti-CD47 Antibody Magrolimab (5F9) in combination with azacitidine is effective in MDS and AML patients: ongoing phase 1b results. Blood. 2019;134(Supplement_1):569–569.
   Web of Science ®Google Scholar
• Borate U, Esteve J, Porkka K, et al. Phase Ib study of the anti-TIM-3 antibody MBG453 in combination with decitabine in patients with high-risk Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML). Blood. 2019;134(Supplement_1):570–570.
   Web of Science ®Google Scholar
• Zeidan AM, Miyazaki Y, Platzbecker U, et al. A randomized, double-blind, placebo-controlled, phase II study of MBG453 added to Hypomethylating Agents (HMAs) in Patients (pts) with intermediate, high, or very high risk Myelodysplastic Syndrome (MDS): Stimulus-MDS1. Blood. 2019;134(Supplement_1):4259–4259.
   Web of Science ®Google Scholar
• Garcia-Manero G, Jonasova A, Luger SM, et al. Genomic profiling in patients with Higher-Risk Myelodysplastic Syndrome (HR-MDS) following hma failure: baseline results from the inspire study (04–30). Blood. 2019;134(Supplement_1):3015–3015.
   Web of Science ®Google Scholar
• Moyo TK, Watts JM, Skikne BS, et al. Preliminary results from a Phase II study of the combination of pevonedistat and azacitidine in the treatment of MDS and MDS/MPN after failure of DNA methyltransferase inhibition. Blood. 2019;134(Supplement_1):4236–4236.
   Web of Science ®Google Scholar
• Wei AH, Garcia JS, Borate U, et al. A phase 1b study evaluating the safety and efficacy of venetoclax in combination with azacitidine in treatment-Naïve patients with higher-risk myelodysplastic syndrome. Blood. 2019;134(Supplement_1):568–568.
   PubMed Web of Science ®Google Scholar
• Zeidan AM, Pollyea DA, Garcia JS, et al. A Phase 1b study evaluating the safety and efficacy of venetoclax as monotherapy or in combination with azacitidine for the treatment of relapsed/refractory myelodysplastic syndrome. Blood. 2019;134(Supplement_1):565–565.
   Web of Science ®Google Scholar
• Garcia-Manero G, Roboz G, Walsh K, et al. Guadecitabine (SGI-110) in patients with intermediate or high-risk myelodysplastic syndromes: phase 2 results from a multicentre, open-label, randomised, phase 1/2 trial. Lancet Haematol. 2019;6(6):e317–e327.
   PubMed Web of Science ®Google Scholar
• Roboz GJ, Kantarjian HM, Yee KWL, et al. Dose, schedule, safety, and efficacy of guadecitabine in relapsed or refractory acute myeloid leukemia. Cancer. 2018;124(2):325–334.
   PubMed Web of Science ®Google Scholar
• Kantarjian HM, Roboz GJ, Kropf PL, et al. Guadecitabine (SGI-110) in treatment-naive patients with acute myeloid leukaemia: phase 2 results from a multicentre, randomised, phase 1/2 trial. Lancet Oncol. 2017;18(10):1317–1326.
   PubMed Web of Science ®Google Scholar
• Issa JJ, Roboz G, Rizzieri D, et al. Safety and tolerability of guadecitabine (SGI-110) in patients with myelodysplastic syndrome and acute myeloid leukaemia: a multicentre, randomised, dose-escalation phase 1 study. Lancet Oncol. 2015;16(9):1099–1110.
   PubMed Web of Science ®Google Scholar
• Fenaux P, Gobbi MK, Patricia L, et al. Results of ASTRAL-1 study, a phase 3 randomized trial of Guadecitabine (G) VS Treatment Choice (TC) in Treatment Naïve Acute Myeloid Leukemia (TN-AML) not eligible for Intensive Chemotherapy (IC). EHA. 2019;267462(S879):267462.
   Google Scholar
• Chung W, Kelly AD, Kropf P, et al. Genomic and epigenomic predictors of response to guadecitabine in relapsed/refractory acute myelogenous leukemia. Clin Epigenet. 2019;11(1):106.
   PubMed Web of Science ®Google Scholar
• Savona MR, Kolibaba K, Conkling P, et al. Extended dosing with CC-486 (oral azacitidine) in patients with myeloid malignancies. Am J Hematol. 2018;93(10):1199–1206.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• de Lima M, Oran B, Champlin RE, et al. CC-486 maintenance after stem cell transplantation in patients with acute myeloid leukemia or myelodysplastic syndromes. Biol Blood Marrow Transplant. 2018;24(10):2017–2024.
   PubMed Web of Science ®Google Scholar
• Platzbecker U, Wermke M, Radke J, et al. Azacitidine for treatment of imminent relapse in MDS or AML patients after allogeneic HSCT: results of the RELAZA trial. Leukemia. 2012;26(3):381–389.
   PubMed Web of Science ®Google Scholar
• Wei AH, Döhner H, Pocock C, et al. The QUAZAR AML-001 maintenance trial: results of a phase III international, randomized, double-blind, placebo-controlled study of CC-486 (Oral Formulation of Azacitidine) in Patients with Acute Myeloid Leukemia (AML) in first remission. Blood. 2019;134(Supplement_2):LBA-3–LBA-3.
   Web of Science ®Google Scholar
• Clinicaltrials.gov. Safety and efficacy study of CC-486 in subjects with myelodysplastic syndromes; [cited 2020 Apr 16]. Available from: https://ClinicalTrials.gov/show/NCT02281084.
   Google Scholar
• Savona MR, Odenike O, Amrein PC, et al. An oral fixed-dose combination of decitabine and cedazuridine in myelodysplastic syndromes: a multicentre, open-label, dose-escalation, phase 1 study. Lancet Haematol. 2019;6(4):e194–e203.
   PubMed Web of Science ®Google Scholar
• Garcia-Manero G, Griffiths EA, Roboz GJ, et al. A phase 2 dose-confirmation study of oral ASTX727, a combination of oral decitabine with a Cytidine Deaminase Inhibitor (CDAi) Cedazuridine (E7727), in Subjects with Myelodysplastic Syndromes (MDS). Blood. 2016;128(22):114–4274.
   Web of Science ®Google Scholar
• DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019;133(1):7–17.
   PubMed Web of Science ®Google Scholar
• Wei AH, Strickland SA, Jr., Hou JZ, et al. Venetoclax combined with low-dose cytarabine for previously untreated patients with acute myeloid leukemia: results from a phase Ib/II study. J Clin Oncol . 2019;37(15):1277–1284.
   PubMed Web of Science ®Google Scholar
• Ram R, Amit O, Zuckerman T, et al. Venetoclax in patients with acute myeloid leukemia refractory to hypomethylating agents-a multicenter historical prospective study. Ann Hematol. 2019;98(8):1927–1932.
   PubMed Web of Science ®Google Scholar
• Jilg S, Hauch RT, Kauschinger J, et al. Venetoclax with azacitidine targets refractory MDS but spares healthy hematopoiesis at tailored dose. Exp Hematol Oncol. 2019;8(1):9–9.
   PubMed Web of Science ®Google Scholar
• Bewersdorf JP, Stahl M, Zeidan AM. Immune checkpoint-based therapy in myeloid malignancies: a promise yet to be fulfilled. Expert Rev Anticancer Ther. 2019;19(5):393–404.
   PubMed Web of Science ®Google Scholar
• Zeidan AM, Knaus HA, Robinson TM, et al. A multi-center Phase I trial of ipilimumab in patients with myelodysplastic syndromes following hypomethylating agent failure. Clin Cancer Res. 2018;24(15):3519–3527.
   PubMed Web of Science ®Google Scholar
• Daver N, Boddu P, Garcia-Manero G, et al. Hypomethylating agents in combination with immune checkpoint inhibitors in acute myeloid leukemia and myelodysplastic syndromes. Leukemia. 2018;32(5):1094–1105.
   PubMed Web of Science ®Google Scholar
• Garcia-Manero G, Sasaki K, Montalban-Bravo G, et al. A phase II study of nivolumab or ipilimumab with or without azacitidine for patients with Myelodysplastic Syndrome (MDS). Blood. 2018;132(Supplement 1):465–465.
   PubMed Web of Science ®Google Scholar
• Garcia-Manero G, Tallman MS, Martinelli G, et al. Pembrolizumab, a PD-1 Inhibitor, in Patients with Myelodysplastic Syndrome (MDS) after failure of hypomethylating agent treatment. Blood. 2016;128(22):345–345.
   Web of Science ®Google Scholar
• Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol. 2013;13(4):227–242.
   PubMed Web of Science ®Google Scholar
• Williams P, Basu S, Garcia-Manero G, et al. The distribution of T-cell subsets and the expression of immune checkpoint receptors and ligands in patients with newly diagnosed and relapsed acute myeloid leukemia. Cancer. 2019;125(9):1470–1481.
   PubMed Web of Science ®Google Scholar
• Rausch CR, Paul S, Montalban Bravo G, et al. Pattern of immune-mediated toxicities in patients with Myelodysplastic Syndrome (MDS) treated with nivolumab and ipilimumab. Blood. 2018;132(Supplement 1):4367–4367.
   Web of Science ®Google Scholar
• Daver N, Garcia-Manero G, Basu S, et al. Efficacy, safety, and biomarkers of response to azacitidine and nivolumab in relapsed/refractory acute myeloid leukemia: a nonrandomized, open-label, Phase II study. Cancer Discov. 2019;9(3):370–383.
   PubMed Web of Science ®Google Scholar
• Chien KS, Borthakur GM, Naqvi K, et al. Updated preliminary results from a phase II study combining azacitidine and pembrolizumab in patients with higher-risk myelodysplastic syndrome. Blood. 2019;134(Supplement_1):4240–4240.
   Web of Science ®Google Scholar
• Komrokji RS, Raza A, Lancet JE, et al. Phase I clinical trial of oral rigosertib in patients with myelodysplastic syndromes. Br J Haematol. 2013;162(4):517–524.
   PubMed Web of Science ®Google Scholar
• Balaian E, Weidner H, Wobus M, et al. Effects of rigosertib on the osteo-hematopoietic niche in myelodysplastic syndromes. Ann Hematol. 2019;98(9):2063–2072.
   PubMed Web of Science ®Google Scholar
• Navada SC, Fruchtman SM, Odchimar-Reissig R, et al. A phase 1/2 study of rigosertib in patients with myelodysplastic syndromes (MDS) and MDS progressed to acute myeloid leukemia. Leuk Res. 2018;64:10–16.
   PubMed Web of Science ®Google Scholar
• Silverman LR, Greenberg P, Raza A, et al. Clinical activity and safety of the dual pathway inhibitor rigosertib for higher risk myelodysplastic syndromes following DNA methyltransferase inhibitor therapy. Hematol Oncol. 2015;33(2):57–66.
   PubMed Web of Science ®Google Scholar
• Garcia-Manero G, Fenaux P, Al-Kali A, et al. Rigosertib versus best supportive care for patients with high-risk myelodysplastic syndromes after failure of hypomethylating drugs (ONTIME): a randomised, controlled, phase 3 trial. The Lancet Oncology. 2016;17(4):496–508.
   PubMed Web of Science ®Google Scholar
• Chaurasia P, Isoda F, Novy T, et al. Rigosertib (RIG) in combination with azacitidine (AZA) to modulate epigenetic effects and to overcome clinical resistance to hypomethylating agents (HMA) in myelodsyplastic syndromes (MDS). J Clin Oncol. 2016;34(15_suppl):7020–7020.
   Web of Science ®Google Scholar
• Navada SC, Garcia-Manero G, Hearn KP, et al. Combination of oral rigosertib and injectable azacitidine in patients with Myelodysplastic Syndromes (MDS): results from a Phase II study. Blood. 2016;128(22):3167–3167.
   Web of Science ®Google Scholar
• Stengel A, Kern W, Haferlach T, et al. The impact of TP53 mutations and TP53 deletions on survival varies between AML, ALL, MDS and CLL: an analysis of 3307 cases. Leukemia. 2017;31(3):705–711.
   PubMed Web of Science ®Google Scholar
• Haase D, Stevenson KE, Neuberg D, et al. TP53 mutation status divides myelodysplastic syndromes with complex karyotypes into distinct prognostic subgroups. Leukemia. 2019;33(7):1747–1758.
   PubMed Web of Science ®Google Scholar
• Sallman DA, DeZern AE, Steensma DP, et al. Phase 1b/2 combination study of APR-246 and Azacitidine (AZA) in patients with TP53 mutant Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML). Blood. 2018;132(Supplement 1):3091–3091.
   Google Scholar
• Lehmann S, Bykov VJ, Ali D, et al. Targeting p53 in vivo: a first-in-human study with p53-targeting compound APR-246 in refractory hematologic malignancies and prostate cancer. J Clin Oncol. 2012;30(29):3633–3639.
   PubMed Web of Science ®Google Scholar
• Sallman DA, DeZern AE, Garcia-Manero G, et al. Phase 2 results of APR-246 and Azacitidine (AZA) in patients with TP53 mutant Myelodysplastic Syndromes (MDS) and Oligoblastic Acute Myeloid Leukemia (AML). Blood. 2019;134(Supplement_1):676–676.
   Web of Science ®Google Scholar
• Cluzeau T, Sebert M, Rahmé R, et al. APR-246 Combined with Azacitidine (AZA) in TP53 Mutated Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML). a Phase 2 Study By the Groupe Francophone Des Myélodysplasies (GFM). Blood. 2019;134(Supplement_1):677–677.
   Web of Science ®Google Scholar
• Dawson MA, Kouzarides T. Cancer epigenetics: from mechanism to therapy. Cell. 2012;150(1):12–27.
   PubMed Web of Science ®Google Scholar
• Bewersdorf JP, Shallis R, Stahl M, et al. Epigenetic therapy combinations in acute myeloid leukemia: what are the options? Ther Adv Hematol. 2019;10:204062071881669. 2040620718816698.
   Web of Science ®Google Scholar
• Prebet T, Sun Z, Figueroa ME, 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. J Clin Oncol. 2014;32(12):1242–1248.
   PubMed Web of Science ®Google Scholar
• Prebet T, Sun Z, Ketterling RP, 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;172(3):384–391.
   PubMed Web of Science ®Google Scholar
• Sekeres MA, Othus M, List AF, 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;35(24):2745–2753.
   PubMed Web of Science ®Google Scholar
• Garcia-Manero G, Montalban-Bravo G, Berdeja JG, et al. Phase 2, randomized, double-blind study of pracinostat in combination with azacitidine in patients with untreated, higher-risk myelodysplastic syndromes. Cancer. 2017;123(6):994–1002.
   PubMed Web of Science ®Google Scholar
• Lin JJ, Milhollen MA, Smith PG, et al. NEDD8-targeting drug MLN4924 elicits DNA rereplication by stabilizing Cdt1 in S phase, triggering checkpoint activation, apoptosis, and senescence in cancer cells. Cancer Res. 2010;70(24):10310–10320.
   PubMed Web of Science ®Google Scholar
• Swords RT, Erba HP, DeAngelo DJ, et al. Pevonedistat (MLN4924), a first-in-class NEDD8-activating enzyme inhibitor, in patients with acute myeloid leukaemia and myelodysplastic syndromes: a phase 1 study. Br J Haematol. 2015;169(4):534–543.
   PubMed Web of Science ®Google Scholar
• Swords RT, Watts J, Erba HP, et al. Expanded safety analysis of pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, in patients with acute myeloid leukemia and myelodysplastic syndromes. Blood Cancer J. 2017;7(2):e520–e520.
   PubMed Web of Science ®Google Scholar
• Swords RT, Coutre S, Maris MB, et al. Pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, combined with azacitidine in patients with AML. Blood. 2018;131(13):1415–1424.
   PubMed Web of Science ®Google Scholar
• Zhou L, Chen S, Zhang Y, et al. The NAE inhibitor pevonedistat interacts with the HDAC inhibitor belinostat to target AML cells by disrupting the DDR. Blood. 2016;127(18):2219–2230.
   PubMed Web of Science ®Google Scholar
• Bejar R, Stevenson K, Abdel-Wahab O, et al. Clinical effect of point mutations in myelodysplastic syndromes. N Engl J Med. 2011;364(26):2496–2506.
   PubMed Web of Science ®Google Scholar
• Papaemmanuil E, Gerstung M, Malcovati L, et al. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood. 2013;122(22):3616–3627; quiz 3699.
   PubMed Web of Science ®Google Scholar
• Medeiros BC, Fathi AT, DiNardo CD, et al. Isocitrate dehydrogenase mutations in myeloid malignancies. Leukemia. 2017;31(2):272–281.
   PubMed Web of Science ®Google Scholar
• Stein EM, Fathi AT, DiNardo CD, et al. Enasidenib (AG-221), a potent oral inhibitor of mutant isocitrate dehydrogenase 2 (IDH2) enzyme, induces hematologic responses in patients with Myelodysplastic Syndromes (MDS). Blood. 2016;128(22):343–343.
   Web of Science ®Google Scholar
• Richard-Carpentier G, DeZern AE, 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(Supplement_1):678–678.
   PubMed Web of Science ®Google Scholar
• DiNardo CD, Watts JM, Stein EM, 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(Supplement 1):1812–1812.
   Web of Science ®Google Scholar
• Megías-Vericat JE, Ballesta-López O, Barragán E, et al. IDH1-mutated relapsed or refractory AML: current challenges and future prospects. Blood lymphatic cancer: targets therapy. 2019;Volume 9:19–32.
   Web of Science ®Google Scholar
• Cortes JE, Wang ES, Watts JM, et al. Olutasidenib (FT-2102) induces rapid remissions in patients with IDH1-mutant myelodysplastic syndrome: results of phase 1/2 single agent treatment and combination with Azacitidine. Blood. 2019;134(Supplement_1):674–674.
   Web of Science ®Google Scholar
• Traina F, Visconte V, Elson P, et al. Impact of molecular mutations on treatment response to DNMT inhibitors in myelodysplasia and related neoplasms. Leukemia. 2014;28(1):78–87.
   PubMed Web of Science ®Google Scholar
• Itzykson R, Kosmider O, Cluzeau T, et al. Impact of TET2 mutations on response rate to azacitidine in myelodysplastic syndromes and low blast count acute myeloid leukemias. Leukemia. 2011;25(7):1147–1152.
   PubMed Web of Science ®Google Scholar
• Liu Y, Bewersdorf JP, Stahl M, et al. Immunotherapy in acute myeloid leukemia and myelodysplastic syndromes: the dawn of a new era? Blood Rev. 2019;34:67–83.
   PubMed Web of Science ®Google Scholar
• Cheson BD, Greenberg PL, Bennett JM, et al. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006;108(2):419–425.
   PubMed Web of Science ®Google Scholar
• Komrokji RS, DeZern AE, Zell K, et al. Validation of International Working Group (IWG) response criteria in higher-risk Myelodysplastic Syndromes (MDS): a report on behalf of the MDS Clinical Research Consortium (MDS CRC). Blood. 2015;126(23):909–909.
   Web of Science ®Google Scholar