Treatment of myelodysplastic syndromes in the era of precision medicine and immunomodulatory drugs: a focus on higher-risk disease

Zeidan AM, Shallis RM, Wang R, Davidoff A, Ma X. Epidemiology of myelodysplastic syndromes: why characterizing the beast is a prerequisite to taming it. Blood Rev. 2019;34:1–15.

PubMed  Article  Google Scholar 

Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A, 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):223–32.

CAS  PubMed  PubMed Central  Article  Google Scholar 

Mozessohn L, Cheung MC, Fallahpour S, Gill T, Maloul A, Zhang L, et al. Azacitidine in the “real-world”: an evaluation of 1101 higher-risk myelodysplastic syndrome/low blast count acute myeloid leukaemia patients in Ontario, Canada. Br J Haematol. 2018;181(6):803–15.

CAS  PubMed  Article  Google Scholar 

Zeidan AM, Wang R, Gross CP, Gore SD, Huntington SF, Prebet T, et al. Modest improvement in survival of patients with refractory anemia with excess blasts in the hypomethylating agents era in the United States. Leuk Lymphoma. 2017;58(4):982–5.

PubMed  Article  Google Scholar 

Zeidan AM, Davidoff AJ, Long JB, Hu X, Wang R, Ma X, et al. Comparative clinical effectiveness of azacitidine versus decitabine in older patients with myelodysplastic syndromes. Br J Haematol. 2016;175(5):829–40.

CAS  PubMed  Article  Google Scholar 

Zeidan AM, Sekeres MA, Garcia-Manero G, Steensma DP, Zell K, Barnard J, et al. Comparison of risk stratification tools in predicting outcomes of patients with higher-risk myelodysplastic syndromes treated with azanucleosides. Leukemia. 2016;30(3):649–57.

CAS  PubMed  Article  Google Scholar 

Prébet T, Gore SD, Esterni B, Gardin C, Itzykson R, Thepot S, et al. Outcome of high-risk myelodysplastic syndrome after Azacitidine treatment failure. J Clin Oncol. 2011;29(24):3322–7.

PubMed  PubMed Central  Article  CAS  Google Scholar 

Zeidan AM, Stahl M, Hu X, Wang R, Huntington SF, Podoltsev NA, et al. Long-term survival of older patients with MDS treated with HMA therapy without subsequent stem cell transplantation. Blood. 2018;131(7):818–21.

CAS  PubMed  PubMed Central  Article  Google Scholar 

Pleyer L, Burgstaller S, Stauder R, Girschikofsky M, Sill H, Schlick K, et al. Azacitidine front-line in 339 patients with myelodysplastic syndromes and acute myeloid leukaemia: comparison of French-American-British and World Health Organization classifications. J Hematol Oncol. 2016;9:39.

PubMed  PubMed Central  Article  CAS  Google Scholar 

Papaemmanuil E, Gerstung M, Malcovati L, Tauro S, Gundem G, Van Loo P, et al. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood. 2013;122(22):3616–27; quiz 99.

Steensma DP, Brunner AM, DeZern AE, Garcia-Manero G, Komrokji RS, Odenike OS, et al. Low clinical trial accrual of patients with myelodysplastic syndromes: causes and potential solutions. Cancer. 2018;124(24):4601–9.

PubMed  Article  Google Scholar 

Bewersdorf JP, Zeidan AM. Management of higher risk myelodysplastic syndromes after hypomethylating agents failure: are we about to exit the black hole? Expert Rev Hematol. 2020;13(10):1131–42.

CAS  PubMed  Article  Google Scholar 

Bewersdorf JP, Zeidan AM. Following in the footsteps of acute myeloid leukemia: are we witnessing the start of a therapeutic revolution for higher-risk myelodysplastic syndromes? Leuk Lymphoma. 2020;61(10):2295–312.

CAS  PubMed  PubMed Central  Article  Google Scholar 

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;35(24):2745–53.

CAS  PubMed  PubMed Central  Article  Google Scholar 

Greenberg PL, Garcia-Manero G, Moore M, Damon L, Roboz G, Hu K, et al. A randomized controlled trial of romiplostim in patients with low- or intermediate-risk myelodysplastic syndrome receiving decitabine. Leuk Lymphoma. 2013;54(2):321–8.

CAS  PubMed  Article  Google Scholar 

Platzbecker U, Scherres W, Guo Z, Calvo R, Germing U. Phase I study of volasertib combined with azacitidine in patients with previously untreated, high-risk myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML) ineligible for high-intensity therapy. Clin Lymphoma Myeloma Leuk. 2015;15:S233.

Article  Google Scholar 

Garcia-Manero G, Montalban-Bravo G, Berdeja JG, Abaza Y, Jabbour E, Essell J, 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.

CAS  PubMed  Article  Google Scholar 

Zeidan AM, Cavenagh J, Voso MT, Taussig D, Tormo M, Boss I, et al. Efficacy and Safety of Azacitidine (AZA) in Combination with the Anti-PD-L1 Durvalumab (durva) for the Front-Line Treatment of Older Patients (pts) with Acute Myeloid Leukemia (AML) Who Are Unfit for Intensive Chemotherapy (IC) and Pts with Higher-Risk Myelodysplastic Syndromes (HR-MDS): Results from a Large, International, Randomized Phase 2 Study. Blood. 2019;134(Supplement_1):829-.

Shreve J, Nazha A. The evolving landscape of myelodysplastic syndrome prognostication. Clin Hematol Int. 2020;2(2):43–8.

PubMed  PubMed Central  Article  Google Scholar 

Canaani J. Emerging therapies for the myelodysplastic syndromes. Clin Hematol Int. 2020;2(1):13–7.

PubMed  Article  Google Scholar 

Bannon SA, DiNardo CD. Hereditary predispositions to myelodysplastic syndrome. Int J Mol Sci. 2016;17(6):838.

PubMed Central  Article  CAS  Google Scholar 

Lancet JE, Uy GL, Cortes JE, Newell LF, Lin TL, Ritchie EK, 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):2684–92.

CAS  PubMed  PubMed Central  Article  Google Scholar 

Peterlin P, Turlure P, Chevallier P, Gourin M-P, Dumas P-Y, Thepot S, et al. CPX 351 as first line treatment in higher risk MDS. A Phase II trial by the GFM. Blood. 2021;138(Supplement 1):243.

Article  Google Scholar 

Dhillon S. Decitabine/cedazuridine: first approval. Drugs. 2020;80(13):1373–8.

CAS  PubMed  Article  Google Scholar 

Garcia-Manero G, Griffiths EA, Steensma DP, Roboz GJ, Wells R, McCloskey J, et al. Oral cedazuridine/decitabine for MDS and CMML: a phase 2 pharmacokinetic/pharmacodynamic randomized crossover study. Blood. 2020;136(6):674–83.

CAS  PubMed  PubMed Central  Article  Google Scholar 

Savona MR, Odenike O, Amrein PC, Steensma DP, DeZern AE, Michaelis LC, 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):e194–203.

PubMed  Article  Google Scholar 

Guillermo Garcia-Manero M, James McCloskey M, Elizabeth A. Griffiths M, Karen W.L. Yee M, Amer M. Zeidan M, MHS, Aref Al-Kali M, 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;134:846.

Astex Pharamceuticals presents overall survival data from ASCERTAIN phase 3 study of oral hypomethylating agent Inqovi (decitabine and cedazuridine) in MDS and CMML at International Congress on Myelodysplastic Syndromes News release. : Astex Pharmaceuticals. ; [updated September 23, 2021. Available from: https://bit.ly/3m0nzJ9.

Savona MR MJ, Griffiths EA, et al. Prolonged survival observed in 133 MDS patients treated with oral decitabine/cedazuridine. Presented at: 16th International Congress on Myelodysplastic Syndromes 2021 [updated September 23–26. Available from: https://bit.ly/3ENe1cV.

Venugopal S, Kantarjian H, Maiti A, Short NJ, Montalban-Bravo G, Alvarado Y, et al. A Phase I/II study of venetoclax in combination with ASTX727 (cedazuridine/decitabine) in treatment‐Naïve high‐risk myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML). Blood. 2021;138(Supplement 1):245.

Garcia-Manero G, Santini V, Almeida A, Platzbecker U, Jonasova A, Silverman LR, et al. Phase III, randomized, placebo-controlled trial of CC-486 (oral azacitidine) in patients with lower-risk myelodysplastic syndromes. J Clin Oncol. 2021;39(13):1426–36.

CAS  PubMed  PubMed Central  Article  Google Scholar 

Konopleva M, Pollyea DA, Potluri J, Chyla B, Hogdal L, Busman T, et al. Efficacy and biological correlates of response in a Phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discov. 2016;6(10):1106–17.

CAS  PubMed  PubMed Central  Article  Google Scholar 

Reidel V, Kauschinger J, Hauch RT, Muller-Thomas C, Nadarajah N, Burgkart R, et al. Selective inhibition of BCL-2 is a promising target in patients with high-risk myelodysplastic syndromes and adverse mutational profile. Oncotarget. 2018;9(25):17270–81.

PubMed  PubMed Central  Article  Google Scholar 

DiNardo CD, Jonas BA, Pullarkat V, Thirman MJ, Garcia JS, Wei AH, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383(7):617–29.

CAS  PubMed  Article  Google Scholar 

Feld J, Tremblay D, Dougherty M, Czaplinska T, Sanchez G, Brady C, et al. Safety and efficacy: clinical experience of venetoclax in combination with hypomethylating agents in both newly diagnosed and relapsed/refractory advanced myeloid malignancies. Hemasphere. 2021;5(4): e549.

CAS  PubMed  PubMed Central  Article  Google Scholar 

Jilg S, Hauch RT, Kauschinger J, Buschhorn L, Odinius TO, Dill V, et al. Venetoclax with azacitidine targets refractory MDS but spares healthy hematopoiesis at tailored dose. Exp Hematol Oncol. 2019;8:9.

PubMed  PubMed Central  Article  Google Scholar 

Jilg S, Reidel V, Muller-Thomas C, Konig J, Schauwecker J, Hockendorf U, et al. Blockade of BCL-2 proteins efficiently induces apoptosis in progenitor cells of high-risk myelodysplastic syndromes patients. Leukemia. 2016;30(1):112–23.

CAS  PubMed  Article  Google Scholar 

Garcia JS, Wei AH, Jacoby MA, Fong CY, Borate U, Baer MR, et al. Molecular responses are observed across mutational spectrum in treatment-naïve higher-risk myelodysplastic syndrome patients treated with venetoclax plus azacitidine. Blood. 2021;138(Supplement 1):241.

Article  Google Scholar 

Garcia JS, Wei AH, Borate U, Fong CY, Baer MR, Nolte F, et al. Safety, efficacy, and patient-reported outcomes of venetoclax in combination with azacitidine for the treatment of patients with higher-risk myelodysplastic syndrome: A Phase 1b study. Blood. 2020;136(Supplement 1):55–7.

Article  Google Scholar 

Zeidan AM, Garcia JS, Fenaux P, Platzbecker U, Miyazaki Y, Xiao Z-J, et al. Phase 3 VERONA study of venetoclax with azacitidine to assess change in complete remission and overall survival in treatment-naïve higher-risk myelodysplastic syndromes. J Clin Oncol. 2021;39(15_suppl):TPS7054-TPS.

Fenaux P, Platzbecker U, Ades L. How we manage adults with myelodysplastic syndrome. Br J Haematol. 2020;189(6):1016–27.

CAS  PubMed  Article  Google Scholar 

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