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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

Tobiasson, M.; Dybedahl, I.; Holm, M. S.; Karimi, M.; Brandefors, L.; Garelius, H.; Grövdal, M.; Högh-Dufva, I.; Grønbæk, K. and Jansson, M., et al. (2014) In Blood Cancer Journal 4(3).
Abstract

This prospective phase II study evaluated the efficacy of azacitidine (Aza) + erythropoietin (Epo) in transfusion-dependent patients with lower-risk myelodysplastic syndrome (MDS). Patients ineligible for or refractory to full-dose Epo + granulocyte colony stimulation factors for 48 weeks and a transfusion need of ≥ 4 units over 8 weeks were included. Aza 75mgm -2 d-1, 5/28 days, was given for six cycles; non-responding patients received another three cycles combined with Epo 60 000 units per week. Primary end point was transfusion independence (TI). All patients underwent targeted mutational screen for 42 candidate genes. Thirty enrolled patients received ≥ one cycle of Aza. Ten patients discontinued the study... (More)

This prospective phase II study evaluated the efficacy of azacitidine (Aza) + erythropoietin (Epo) in transfusion-dependent patients with lower-risk myelodysplastic syndrome (MDS). Patients ineligible for or refractory to full-dose Epo + granulocyte colony stimulation factors for 48 weeks and a transfusion need of ≥ 4 units over 8 weeks were included. Aza 75mgm -2 d-1, 5/28 days, was given for six cycles; non-responding patients received another three cycles combined with Epo 60 000 units per week. Primary end point was transfusion independence (TI). All patients underwent targeted mutational screen for 42 candidate genes. Thirty enrolled patients received ≥ one cycle of Aza. Ten patients discontinued the study early, 7 due to adverse events including 2 deaths. Thirty-eight serious adverse events were reported, the most common being infection. Five patients achieved TI after six cycles and one after Aza + Epo, giving a total response rate of 20%. Mutational screening revealed a high frequency of recurrent mutations. Although no single mutation predicted for response, SF3A1 (n = 3) and DNMT3A (n = 4) were only observed in nonresponders. We conclude that Aza can induce TI in severely anemic MDS patients, but efficacy is limited, toxicity substantial and most responses of short duration. This treatment cannot be generally recommended in lower-risk MDS. Mutational screening revealed a high frequency of mutations.

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Blood Cancer Journal
volume
4
issue
3
publisher
Nature Publishing Group
external identifiers
  • scopus:84901839639
  • pmid:24608733
ISSN
2044-5385
DOI
10.1038/bcj.2014.8
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English
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3af48dc4-94a8-40d3-aa6f-b61822d43b11
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2019-05-22 09:51:07
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2019-07-30 05:01:55
@article{3af48dc4-94a8-40d3-aa6f-b61822d43b11,
  abstract     = {<p>This prospective phase II study evaluated the efficacy of azacitidine (Aza) + erythropoietin (Epo) in transfusion-dependent patients with lower-risk myelodysplastic syndrome (MDS). Patients ineligible for or refractory to full-dose Epo + granulocyte colony stimulation factors for 48 weeks and a transfusion need of ≥ 4 units over 8 weeks were included. Aza 75mgm <sup>-2</sup> d<sup>-1</sup>, 5/28 days, was given for six cycles; non-responding patients received another three cycles combined with Epo 60 000 units per week. Primary end point was transfusion independence (TI). All patients underwent targeted mutational screen for 42 candidate genes. Thirty enrolled patients received ≥ one cycle of Aza. Ten patients discontinued the study early, 7 due to adverse events including 2 deaths. Thirty-eight serious adverse events were reported, the most common being infection. Five patients achieved TI after six cycles and one after Aza + Epo, giving a total response rate of 20%. Mutational screening revealed a high frequency of recurrent mutations. Although no single mutation predicted for response, SF3A1 (n = 3) and DNMT3A (n = 4) were only observed in nonresponders. We conclude that Aza can induce TI in severely anemic MDS patients, but efficacy is limited, toxicity substantial and most responses of short duration. This treatment cannot be generally recommended in lower-risk MDS. Mutational screening revealed a high frequency of mutations.</p>},
  articleno    = {e189},
  author       = {Tobiasson, M. and Dybedahl, I. and Holm, M. S. and Karimi, M. and Brandefors, L. and Garelius, H. and Grövdal, M. and Högh-Dufva, I. and Grønbæk, K. and Jansson, M. and Marcher, C. and Nilsson, L. and Kittang, A. O. and Porwit, A. and Saft, L. and Möllgård, L. and Hellström-Lindberg, E.},
  issn         = {2044-5385},
  language     = {eng},
  month        = {03},
  number       = {3},
  publisher    = {Nature Publishing Group},
  series       = {Blood Cancer Journal},
  title        = {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},
  url          = {http://dx.doi.org/10.1038/bcj.2014.8},
  volume       = {4},
  year         = {2014},
}