Baseline and serial molecular profiling predicts outcomes with hypomethylating agents in myelodysplastic syndromes
Open accessAbstract
Hypomethylating agents (HMAs) are widely used in the treatment of myelodysplastic syndromes (MDSs), yet identifying those patients unlikely to benefit remains challenging. We assessed response and overall survival (OS) in 247 patients molecularly profiled by next-generation sequencing (NGS) before first-line HMA therapy, and a subset of 108 patients were sequenced serially during treatment. The most common mutations included TP53 (33.1%), ASXL1 (19%), TET2 (16.5%), DNMT3A (14.1%), and SRSF2 (12.1%). The overall response rate was 42.1%, with the composite TET2-mutant/ASXL1 wild-type genotype representing the strongest predictor of response (overall response rate, 62.1%; complete remission rate, 34.5%). The median OS for the cohort was 15 months, and the number of mutations detected by NGS (hazard ratio [HR], 1.22; P = .02), as well as mutations in TP53 (HR, 2.33; P = .001) and EZH2 (HR, 2.41; P = .04) were identified as independent covariates associated with inferior OS in multivariable analysis. Serial molecular profiling revealed that clearance of TP53 mutations during HMA therapy was associated with superior OS (HR, 0.28; P = .001) and improved outcome in patients proceeding to allogeneic hematopoietic cell transplantation. These data support baseline molecular profiling by NGS in MDS patients treated with HMAs and provide novel observations of sequential profiling during therapy that provide particular value in TP53-mutated disease.
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In mTP53 mutant MDS with HMA, the CR rate is ~20% with a median OS of less than 12 months.
“In mTP53 mutant MDS with HMA, the CR rate is ~20% with a median OS of less than 12 months.”
From Long‐term follow‐up and combined Phase 2 results of eprenetapopt and azacitidine in patients with <i>TP53</i> mutant MDS/AML (2025) · cites this paper as [17]
Our study validates prior work identifying TP53 VAF clearance to <5% as a predictor for OS in this molecular subgroup.
“notably validates prior work identifying TP53 VAF clearance to <5% as a predictor for OS in this molecular subgroup.”
From Long‐term follow‐up and combined Phase 2 results of eprenetapopt and azacitidine in patients with <i>TP53</i> mutant MDS/AML (2025) · cites this paper as [17]
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Cites
Fenaux, P., Mufti, G. J., Hellstrom-Lindberg, E., Santini, V., Finelli, C., Giagounidis, A., Schoch, R., Gattermann, N., Sanz, G., List, A., et al. (2009) · The Lancet Oncology · doi:10.1016/s1470-2045(09)70003-8 · Cited by 2,663 · see citing works
Self-citationFrequent pathway mutations of splicing machinery in myelodysplasia
Yoshida, K., Sanada, M., Shiraishi, Y., Nowak, D., Nagata, Y., Yamamoto, R., Sato, Y., Sato-Otsubo, A., Kon, A., Nagasaki, M., et al. (2011) · Nature · doi:10.1038/nature10496 · Cited by 2,029 · see citing works
Clinical and biological implications of driver mutations in myelodysplastic syndromes
Papaemmanuil, E., Gerstung, M., Malcovati, L., Tauro, S., Gundem, G., Van Loo, P., Yoon, C. J., Ellis, P., Wedge, D. C., Pellagatti, A., et al. (2013) · Blood · doi:10.1182/blood-2013-08-518886 · Cited by 1,832 · see citing works
Clinical Effect of Point Mutations in Myelodysplastic Syndromes
Bejar, R., Stevenson, K., Abdel-Wahab, O., Galili, N., Nilsson, B., Garcia-Manero, G., Kantarjian, H., Raza, A., Levine, R. L., Neuberg, D., et al. (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1013343 · Cited by 1,627 · see citing works
Cheson, B. D. (2006) · Blood · doi:10.1182/blood-2005-10-4149 · Cited by 1,580 · see citing works
Landscape of genetic lesions in 944 patients with myelodysplastic syndromes
Haferlach, T., Nagata, Y., Grossmann, V, Okuno, Y., Bacher, U., Nagae, G., Schnittger, S., Sanada, M., Kon, A., Alpermann, T., et al. (2014) · Leukemia · doi:10.1038/leu.2013.336 · Cited by 1,532 · see citing works
Decitabine improves patient outcomes in myelodysplastic syndromes
Kantarjian, H. M., Issa, J. J., Rosenfeld, C. S., Bennett, J. M., Albitar, M. X., DiPersio, J. F., Klimek, V. M., Slack, J. L., de Castro, C., Ravandi, F., et al. (2006) · Cancer · doi:10.1002/cncr.21792 · Cited by 1,530 · see citing works
<i>TP53</i> and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes
Welch, J. S., Petti, A. A., Miller, C. A., Fronick, C. C., O’Laughlin, M., Fulton, R. S., Wilson, R. K., Baty, J. D., Duncavage, E. J., Tandon, B., et al. (2016) · New England Journal of Medicine · doi:10.1056/nejmoa1605949 · Cited by 796 · see citing works
Molecular Minimal Residual Disease in Acute Myeloid Leukemia
Jongen‐Lavrencic, M., Grob, T., Hanekamp, D., Kavelaars, F. G., Hinai, A. S. A. A., Zeilemaker, A., Erpelinck-Verschueren, C. A. J., Gradowska, P. L., Meijer, R. J., Cloos, J. J., et al. (2018) · New England Journal of Medicine · doi:10.1056/nejmoa1716863 · Cited by 783 · see citing works
Prognostic Mutations in Myelodysplastic Syndrome after Stem-Cell Transplantation
Lindsley, R. C., Saber, W., Mar, B. G., Redd, R., Wang, T., Haagenson, M. D., Grauman, P. V., Hu, Z.-H., Spellman, S. R., Lee, S. J., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1611604 · Cited by 776 · see citing works
Acquired mutations in TET2 are common in myelodysplastic syndromes
Langemeijer, S. M. C., Kuiper, R. P., Berends, M., Knops, R., Aslanyan, M. G., Massop, M., Stevens-Linders, E., van Hoogen, P., van Kessel, A. G., Raymakers, R. A. P., et al. (2009) · Nature Genetics · doi:10.1038/ng.391 · Cited by 755 · see citing works
TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients
Bejar, R. L., Lord, A. M., Stevenson, K. E., Bar‐Natan, M., Pérez-Ladaga, A., Zaneveld, J. E., Wang, H., Caughey, B. A., Stojanov, P., Getz, G. A., et al. (2014) · Blood · doi:10.1182/blood-2014-06-582809 · Cited by 563 · see citing works
Recurrent DNMT3A mutations in patients with myelodysplastic syndromes
Walter, M. J., Ding, L., Shen, D., Shao, J., Grillot, M., McLellan, M., Fulton, R., Schmidt, H., Kalicki-Veizer, J., O'Laughlin, M., et al. (2011) · Leukemia · doi:10.1038/leu.2011.44 · Cited by 527 · see citing works
Outcome of High-Risk Myelodysplastic Syndrome After Azacitidine Treatment Failure
Prébet, T., Gore, S. D., Esterni, B., Gardin, C., Itzykson, R., Thepot, S., Dreyfus, F., Rauzy, O. B., Recher, C., Adès, L., et al. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2011.35.8135 · Cited by 475 · see citing works
Itzykson, R., Kosmider, O., Cluzeau, T., Mas, V. M., Dreyfus, F., Beyne‐Rauzy, O., Quesnel, B., Vey, N., Gelsi‐Boyer, V., Raynaud, S., et al. (2011) · Leukemia · doi:10.1038/leu.2011.71 · Cited by 470 · see citing works
Landscape Of Genetic Lesions In 944 Patients With Myelodysplastic Syndromes
Nagata, Y., Grossmann, V., Okuno, Y., Bacher, U., Nagae, G., Schnittger, S., Shiozawa, Y., Kon, A., Alpermann, T., Yoshida, K., et al. (2013) · Blood · doi:10.1182/blood.v122.21.521.521 · Cited by 430 · see citing works
Dynamics of clonal evolution in myelodysplastic syndromes
Makishima, H., Yoshizato, T., Yoshida, K., Sekeres, M. A., Radivoyevitch, T., Suzuki, H., Przychodzen, B. P., Nagata, Y., Meggendorfer, M., Sanada, M., et al. (2016) · Nature Genetics · doi:10.1038/ng.3742 · Cited by 420 · see citing works
Bejar, R. L., Stevenson, K. E., Caughey, B. A., Lindsley, R. C., Mar, B. G., Stojanov, P., Getz, G. A., Steensma, D. P., Ritz, J., Soiffer, R. J., et al. (2014) · Journal of Clinical Oncology · doi:10.1200/jco.2013.52.3381 · Cited by 396 · see citing works
Steensma, D. P., Baer, M. R., Slack, J. L., Buckstein, R. J., Godley, L. A., Garcia‐Manero, G., Albitar, M. X., Larsen, J. S., Arora, S., Cullen, M. T., et al. (2009) · Journal of Clinical Oncology · doi:10.1200/jco.2008.19.6550 · Cited by 319 · see citing works
Traina, F., Visconte, V., Elson, P. J., Tabarroki, A., Jankowska, A., Hasrouni, E., Sugimoto, Y., Szpurka, H., Makishima, H., O'Keefe, C., et al. (2013) · Leukemia · doi:10.1038/leu.2013.269 · Cited by 289 · see citing works
Porta, M. G. D., Gallì, A., Bacigalupo, A. P., Zibellini, S., Bernardi, M., Rizzo, E., Allione, B., Lint, M. T. V., Pioltelli, P. E., Marenco, P., et al. (2016) · Journal of Clinical Oncology · doi:10.1200/jco.2016.67.3616 · Cited by 255 · see citing works
DNMT3A mutations and response to the hypomethylating agent decitabine in acute myeloid leukemia
Metzeler, K. H., Walker, A., Geyer, S. M., Garzon, R., Klisovic, R. B., Bloomfield, C. D., Blum, W. G., & Marcucci, G. (2011) · Leukemia · doi:10.1038/leu.2011.342 · Cited by 208 · see citing works
Clearance of Somatic Mutations at Remission and the Risk of Relapse in Acute Myeloid Leukemia
Morita, K., Kantarjian, H. M., Wang, F., Yan, Y., Bueso-Ramos, C., Sasaki, K., Issa, G. C., Wang, S., Jorgensen, J. L., Song, X., et al. (2018) · Journal of Clinical Oncology · doi:10.1200/jco.2017.77.6757 · Cited by 180 · see citing works
Bally, C., Adès, L., Renneville, A., Sebert, M., Eclache, V., Preudhomme, C., Mozziconacci, M.-J., de The, H., Lehmann-Che, J., & Fenaux, P. (2014) · Leukemia Research · doi:10.1016/j.leukres.2014.03.012 · Cited by 162 · see citing works
Bernal, T., Martínez‐Camblor, P., Sánchez‐García, J., de Paz, R., Luño, E., Nomdedeu, B., Ardanaz, M., Pedro, C., Amigo, M. L., Xicoy, B., et al. (2015) · Leukemia · doi:10.1038/leu.2015.115 · Cited by 108 · see citing works
Dickinson, M. J., Cherif, H., Fenaux, P., Mittelman, M., Verma, A. K., Portella, M. S. O., Burgess, P., Ramos, P. M., Choi, J., & Platzbecker, U. (2018) · Blood · doi:10.1182/blood-2018-06-855221 · Cited by 96 · see citing works
Garcia‐Manero, G., Roboz, G. J., Walsh, K. J., Kantarjian, H. M., Ritchie, E. K., Kropf, P. L., O'Connell, C. L., Tibes, R., Lunin, S. D., Rosenblat, T. L., et al. (2019) · The Lancet Haematology · doi:10.1016/s2352-3026(19)30029-8 · Cited by 95 · see citing works
Kuendgen, A., Müller‐Thomas, C., Lauseker, M., Haferlach, T., Urbaniak, P., Schroeder, T. A., Brings, C., Wulfert, M., Meggendorfer, M., Hildebrandt, B., et al. (2018) · Oncotarget · doi:10.18632/oncotarget.25328 · Cited by 73 · see citing works
Garcia‐Manero, G., Sasaki, K., Bravo, G. M., Daver, N. G., Jabbour, E. J., Alvarado, Y., Dinardo, C. D., Ravandi, F., Borthakur, G. M., Bose, P., et al. (2018) · Blood · doi:10.1182/blood-2018-99-119424 · Cited by 68 · see citing works
Mozessohn, L., Cheung, M. C., Fallahpour, S., Gill, T., Maloul, A., Zhang, L., Lau, O., & Buckstein, R. J. (2018) · British Journal of Haematology · doi:10.1111/bjh.15273 · Cited by 58 · see citing works
Yun, S., Geyer, S. M., Komrokji, R. S., Al Ali, N. H., Song, J., Hussaini, M., Sweet, K. L., Lancet, J. E., List, A. F., Padron, E., et al. (2021) · Leukemia · doi:10.1038/s41375-020-0997-4 · Cited by 49 · see citing works
Self-citationReview of azacitidine trials in Intermediate-2-and High-risk myelodysplastic syndromes
Fenaux, P., & Adès, L. (2009) · Leukemia Research · doi:10.1016/s0145-2126(09)70227-9 · Cited by 48 · see citing works
Mutational correlates of response to hypomethylating agent therapy in acute myeloid leukemia
Coombs, C. C., Sallman, D. A., Devlin, S. M., Dixit, S., Mohanty, A. S., Knapp, K. M., Ali, N. H. A., Lancet, J. E., List, A. F., Komrokji, R. S., et al. (2016) · Haematologica · doi:10.3324/haematol.2016.148999 · Cited by 41 · see citing works
Self-citationFalconi, G., Fabiani, E., Piciocchi, A., Criscuolo, M., Fianchi, L., Lindfors Rossi, E. L., Finelli, C., Cerqui, E., Ottone, T., Molteni, A., et al. (2019) · Leukemia · doi:10.1038/s41375-018-0284-9 · Cited by 39 · see citing works
Mutations in histone modulators are associated with prolonged survival during azacitidine therapy
Tobiasson, M., McLornan, D. P., Karimi, M., Dimitriou, M., Jansson, M., Azenkoud, A. B., Jädersten, M., Lindberg, G., Abdulkadir, H., Kulasekararaj, A. G., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.7899 · Cited by 38 · see citing works
Pollyea, D. A., Raval, A., Kusler, B., Gotlib, J. R., Alizadeh, A. A., & Mitchell, B. S. (2010) · Hematological Oncology · doi:10.1002/hon.976 · Cited by 30 · see citing works
ASXL1 frameshift mutations drive inferior outcomes in CMML without negative impact in MDS
Sallman, D. A., Komrokji, R. S., Cluzeau, T., et al. (2017) · Blood Cancer Journal · doi:10.1038/s41408-017-0004-0 · Cited by 26 · see citing works
Self-citationLee, S., Barnard, J., Dezern, A. E., et al. (2016) · Blood · doi:10.1182/blood.v128.22.297.297 · Cited by 1 · see citing works
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Sallman, D. A., Al Malki, M. M., Asch, A. S., Wang, E. S., Jurcic, J. G., Bradley, T. J., Flinn, I. W., Pollyea, D. A., Kambhampati, S., Tanaka, T. N., et al. (2023) · Journal of Clinical Oncology · doi:10.1200/jco.22.01794 · Cited by 188 · see citing works
Self-citationVersluis, J., Saber, W., Tsai, H. K., Gibson, C. J., Dillon, L. W., Mishra, A., McGuirk, J., Maziarz, R. T., Westervelt, P., Hegde, P., et al. (2023) · Journal of Clinical Oncology · doi:10.1200/jco.23.00866 · Cited by 78 · see citing works
Sallman, D. A., Komrokji, R. S., Dezern, A. E., Sebert, M., Garcia‐Manero, G., Rahmé, R., Winer, E. S., Lehmann‐Che, J., Roboz, G. J., Madelaine, I., et al. (2025) · HemaSphere · doi:10.1002/hem3.70164 · Cited by 20 · see citing works
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- Authors
- Hunter, A. M., Komrokji, R. S., Yun, S., Al Ali, N., Chan, O., Song, J., Hussaini, M., Talati, C., Sweet, K. L., Lancet, J. E., Padron, E., List, A. F., & Sallman, D. A.
- Affiliations
- Emory University (US)
- Malignant Hematology Department and
- Moffitt Cancer Center (US)
- ORCID
- Venue
- Blood Advances
- Publisher
- American Society of Hematology
- Published
- 2021-02-16
- Volume
- 5
- Issue
- 4
- Pages
- 1017-1028
- ISSN
- 2473-9529 (ISSN-L)
- 2473-9537
- PMC
- PMC7903224
- OpenAlex
- W3132690588
- Cited by
- 76
- References
- 38
- Citations by year
- 2026: 8 · 2025: 12 · 2024: 15 · 2023: 18 · 2022: 15 · 2021: 7
- FWCI
- 8.98
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Blood Advances (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Edward P. Evans Foundation
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- myelodysplastic syndrome, hypomethylating agents, molecular profiling, TP53 mutation, ASXL1, TET2, DNMT3A, SRSF2, EZH2, treatment response, overall survival, allogeneic hematopoietic stem cell transplantation, prognostic factors
- MeSH terms
- Humans, Mutation, Myelodysplastic Syndromes, Prognosis, Hematopoietic Stem Cell Transplantation, High-Throughput Nucleotide Sequencing
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