Annals of Hematology

, Volume 84, Supplement 1, pp 61–66 | Cite as

Results of a phase 2 study of valproic acid alone or in combination with all-trans retinoic acid in 75 patients with myelodysplastic syndrome and relapsed or refractory acute myeloid leukemia

  • Andrea Kuendgen
  • Sabine Knipp
  • Frank Fox
  • Corinna Strupp
  • Barbara Hildebrandt
  • Christian Steidl
  • Ulrich Germing
  • Rainer Haas
  • Norbert Gattermann
Original Article


Valproic acid (VPA) inhibits histone deacetylase activity and induces differentiation of acute myeloid leukemia (AML) blasts in vitro. We observed clinical responses to VPA in patients with myelodysplastic syndrome (MDS) and AML. Here, we report follow-up data on 75 patients. Of these, 66 were started on VPA monotherapy, with later addition of all-trans retinoic acid (ATRA) in patients who did not respond or relapsed. Nine patients were treated with VPA + ATRA from the start. Median treatment duration was 4 months for VPA and 2 months for ATRA. Hematological improvement, according to international working group criteria for MDS, was observed in 18 patients (24%). Median response duration was 4 months. ATRA exerted no additional effect in patients receiving the combination from the start or benefited primary VPA nonresponders. However, of ten VPA responders who relapsed, four achieved a second response after addition of ATRA. Response rates were strongly dependent on disease type according to WHO classification. We found a response rate of 52% in MDS patients with a normal blast count (refractory sideroblastic anemia, refractory cytopenia with multilineage dysplasia, and refractory sideroblastic cytopenia with multilineage dysplasia). The response rate was 6% in refractory anemia with excess blasts (I + II), 16% in AML, and 0% in chronic myelomonocytic leukemia. Bone marrow blast count was the only variable that predicted responses. We conclude that VPA is clinically useful in low-risk MDS. For patients with high-risk MDS, VPA may be combined with chemotherapy or demethylating drugs. If patients relapse after an initial response to VPA, ATRA has the potential to induce a prolonged second response.


Valproic acid MDS ATRA Epigenetics HDAC inhibition 


  1. 1.
    Baylin SB (2002) Mechanisms underlying epigenetically mediated gene silencing in cancer. Semin Cancer Biol 12:331–337CrossRefPubMedGoogle Scholar
  2. 2.
    Cameron EE, Bachman KE, Myohanen S et al (1999) Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nat Genet 21:103–107CrossRefPubMedGoogle Scholar
  3. 3.
    Chavez-Blanco A, Segura-Pacheco B, Perez-Cardenas E et al (2005) Histone acetylation and histone deacetylase activity of magnesium valproate in tumor and peripheral blood of patients with cervical cancer. A phase I study. Mol Cancer 4:22CrossRefPubMedGoogle Scholar
  4. 4.
    Cheson BD, Bennett JM, Kantarjian H et al (2000) Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood 96:3671–3674PubMedGoogle Scholar
  5. 5.
    Cheson BD, Bennett JM, Bloomfield CD et al (2003) Revised recommendations of the international working group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol 21:4642–4649CrossRefPubMedGoogle Scholar
  6. 6.
    Cinatl J Jr, Cinatl J, Driever PH et al (1997) Sodium valproate inhibits in vivo growth of human neuroblastoma cells. Anti-Cancer Drugs 8:958–963PubMedCrossRefGoogle Scholar
  7. 7.
    Garcia-Manero G, Kantarjian H, Issa J-P et al (2004) Results of a phase I/II study of the combination of 5-aza-2′-deoxycytidine (DAC) and valproic acid (VPA) in patients with leukaemia. Blood 104(Suppl 1):abstract 263Google Scholar
  8. 8.
    Gottlicher M, Minucci S, Zhu P et al (2001) Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J 20:6969–6978CrossRefPubMedGoogle Scholar
  9. 9.
    Greenberg P, Cox C, LeBeau MM et al (1997) International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89:2079–2088PubMedGoogle Scholar
  10. 10.
    Hellstrom-Lindberg E, Ahlgren T, Beguin Y et al (1998) Treatment of anemia in myelodysplastic syndromes with granulocyte colony-stimulating factor plus erythropoietin: results from a randomized phase II study and long-term follow-up of 71 patients. Blood 92:68–75PubMedGoogle Scholar
  11. 11.
    Jones PL, Veenstra GJ, Wade PA et al (1998) Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat Genet 19:187–191CrossRefPubMedGoogle Scholar
  12. 12.
    Kawagoe R, Kawagoe H, Sano K (2002) Valproic acid induces apoptosis in human leukemia cells by stimulating both caspase-dependent and -independent apoptotic signaling pathways. Leuk Res 26:495–502CrossRefPubMedGoogle Scholar
  13. 13.
    Kramer OH, Zhu P, Ostendorff HP et al (2003) The histone deacetylase inhibitor valproic acid selectively induces proteasomal degradation of HDAC2. EMBO J 22:3411–3420CrossRefPubMedGoogle Scholar
  14. 14.
    Kuendgen A, Strupp C, Aivado M et al (2004) Treatment of myelodysplastic syndromes with valproic acid alone or in combination with all-trans retinoic acid. Blood 104:1266–1269CrossRefPubMedGoogle Scholar
  15. 15.
    List A, Kurtin S, Roe DJ et al (2005) Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med 352:549–557CrossRefPubMedGoogle Scholar
  16. 16.
    Loscher W (2002) Basic pharmacology of valproate: a review after 35 years of clinical use for the treatment of epilepsy. CNS Drugs 16:669–694PubMedCrossRefGoogle Scholar
  17. 17.
    Luo RX, Dean DC (1999) Chromatin remodeling and transcriptional regulation. J Natl Cancer Inst 91:1288–1294CrossRefPubMedGoogle Scholar
  18. 18.
    Marks PA, Richon VM, Rifkind RA (2000) Histone deacetylase inhibitors: inducers of differentiation or apoptosis of transformed cells. J Natl Cancer Inst 92:1210–1216CrossRefPubMedGoogle Scholar
  19. 19.
    Phiel CJ, Zhang F, Huang EY et al (2001) Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem 276:36734–36741CrossRefPubMedGoogle Scholar
  20. 20.
    Redner RL, Wang J, Liu JM (1999) Chromatin remodeling and leukemia: new therapeutic paradigms. Blood 94:417–428PubMedGoogle Scholar
  21. 21.
    Schlenk RF, Frohling S, Dohner H et al; AML Study Group Ulm (2004) Phase III study of all-trans retinoic acid in previously untreated patients 61 years or older with acute myeloid leukemia. Leukemia 18:1798–1803CrossRefPubMedGoogle Scholar
  22. 22.
    Wang J, Saunthararajah Y, Redner RL et al (1999) Inhibitors of histone deacetylase relieve ETO-mediated repression and induce differentiation of AML1-ETO leukemia cells. Cancer Res 59:2766–2769PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Andrea Kuendgen
    • 1
  • Sabine Knipp
    • 1
  • Frank Fox
    • 1
  • Corinna Strupp
    • 1
  • Barbara Hildebrandt
    • 2
  • Christian Steidl
    • 3
  • Ulrich Germing
    • 1
  • Rainer Haas
    • 1
  • Norbert Gattermann
    • 1
  1. 1.Department of Hematology, Oncology, and Clinical ImmunologyHeinrich-Heine-UniversityDüsseldorfGermany
  2. 2.Institute of Human GeneticsHeinrich-Heine-UniversityDüsseldorfGermany
  3. 3.Department of Hematology/OncologyUniversity of GöttingenGöttingenGermany

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