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Encouraging results with the compassionate use of hydralazine/valproate (TRANSKRIP™) as epigenetic treatment for myelodysplastic syndrome (MDS)

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Abstract

The hypomethylating agents azacytidine and decitabine are unaffordable for many patients with MDS. The combination of the DNA methyltransferase inhibitor hydralazine and the histone deacetylase inhibitor valproate has shown preliminary efficacy in MDS. The aim of this study is to evaluate the clinical efficacy and safety of hydralazine/valproate in a case series of MDS patients treated in a compassionate manner. Hydralazine was dosed according to the acetylation genotype of patients (slow acetylators 83 mg daily; fast acetylators 182 mg daily), and valproate was dosed at 30 mg/kg/day. Both drugs were given daily until disease progression. Response and toxicity were evaluated with the International Working Group criteria and CTCAE, version 4, respectively. Survival parameters were estimated with the Kaplan-Meier method. From 2009 to 2012, 14 patients were treated. The median age ± SD was 55.2 ± 19.52 (range 23–87) years. According to the IPSS, cases were graded as intermediate-1 (n = 8/14; 57.2%) or intermediate-2 (n = 6/14; 42.8%). Responses were as follows: five (35.7%) complete response, one (7.1%) partial response, and two (14.28%) became transfusion independent. The mean duration of response ± SD was 60 ± 35.28 months (range 5–94). Three patients progressed to AML. At a median follow-up of 57 months (range 1–106), the median OS was 27 months. At that point, five patients remained on the treatment, one with partial response and four with complete response. The median OS was not reached in the eight patients who saw a clinical benefit from the treatment, in comparison to an OS of 7 months in the six patients who had no treatment. The combination of hydralazine and valproate is safe and effective in MDS, and its further testing is highly desirable.

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References

  1. Arber D, Orazi A, Hasserjian R, Thiele J, Borowitz M, Le Bau M et al (2016) The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 127:2391–2405

    Article  CAS  PubMed  Google Scholar 

  2. Greenberg P, Cox C, LeBeau MM et al (1997) International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89:2079–2088

    CAS  PubMed  Google Scholar 

  3. Garcia Manero G (2015) Myelodysplastic syndromes: 2015 Update on diagnosis, risk stratification and management. Am J Hematol 90:831–841

    Article  PubMed  Google Scholar 

  4. Garcia-Manero G, Fenaux P (2011) Hypomethylating agents and other novel strategies in myelodysplastic syndromes. J Clin Oncol 29:516–523

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Chen L, Kantarjian H, Guo Y et al (2010) DNA methylation predicts survival and response to therapy in patients with myelodysplastic syndromes. J Clin Oncol 28:605–613

    Google Scholar 

  6. Fenaux P, Mufti GJ, Hellstrom-Lindberg E et al (2009) 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 10:223–232

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Silverman LR, Demakos EP, Peterson BL et al (2002) Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol 20:2429–2440

    Article  CAS  PubMed  Google Scholar 

  8. Kantarjian H, Issa JP, Rosenfeld CS et al (2006) Decitabine improves patient outcomes in myelodys-plastic syndromes: results of a phase III randomized study. Cancer 106:1794–1803

    Article  CAS  PubMed  Google Scholar 

  9. Dueñas-Gonzalez A, Coronel J, Cetina L et al (2014) Hydralazine-valproate: a repositioned drug combination for the epigenetic therapy of cancer. Expert Opin Drug Metab Toxicol 10:1433–1444

    Article  PubMed  Google Scholar 

  10. Bauman J, Shaheen M, Verschraegen CF, et. al (2014) A phase I protocol of hydralazine and valproic acid in advanced, previously treated solid cancers. Transl Oncol 7:349–354

  11. Espinoza-Zamora JR, Labardini-Méndez J, Sosa-Espinoza A et al (2017) Efficacy of hydralazine and valproate in cutaneous T-cell lymphoma: a phase II study. Expert Opin Investig Drugs 26:1–7

    Article  Google Scholar 

  12. Candelaria M, Herrera A, Labardini J et al (2011) Hydralazine and magnesium valproate as epigenetic treatment for myelodysplastic syndrome. Preliminary results of a phase-II trial. Ann Hematol 90:379–387

    Article  CAS  PubMed  Google Scholar 

  13. Livak KJ (1999) Allelic discrimination using fluorogenic probes and the 5′ nuclease assay. Genet Anal 14:143–149

    Article  CAS  PubMed  Google Scholar 

  14. Taja-Chayeb L, González-Fierro A, Miguez-Muñoz C et al (2011) Acetylator status and N-acetyltransferase 2 gene polymorphisms; phenotype-genotype correlation with the sulfamethazine test. Pharmacogenet Genomics 21:894–901

    Article  CAS  PubMed  Google Scholar 

  15. Cheson BD, Greenberg PL, Bennett JM et al (2006) Clinical application and proposal for modification of the International Working Group (IWG) criteria in myelodysplasia. Blood 108:419–425

    Article  CAS  PubMed  Google Scholar 

  16. Common Terminology Criteria for Adverse Events (CTCAE). National Cancer Institute. Division of Cancer Treatment & Diagnosis. Available at: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm (January 5th, 2017)

  17. Shahrabi S, Khosravi A, Shahjahani M, Rahim F, Saki N (2016) Genetics and epigenetics of myelodysplastic syndromes and response to drug therapy: new insights. Oncol Rev 10:311

    PubMed  PubMed Central  Google Scholar 

  18. Lee YG, Kim I, Yoon SS et al (2013) Korean Society of Haematology AML/MDS working party. Comparative analysis between azacitidine and decitabine for the treatment of myelodysplastic syndromes. Br J Haematol 161:339–347

    Article  CAS  PubMed  Google Scholar 

  19. Soriano AO, Yang H, Faderl S et al (2007) Safety and clinical activity of the combination of 5-azacytidine, valproic acid, and all-trans retinoic acid in acute myeloid leukemia and myelodysplastic syndrome. Blood 110:2302–2308

    Article  CAS  PubMed  Google Scholar 

  20. Jabbour E, Garcia-Manero G, Cornelison AM et al (2015) The effect of decitabine dose modification and myelosuppression on response and survival in patients with myelodysplastic syndromes. Leuk Lymphoma 56:390–394

    Article  CAS  PubMed  Google Scholar 

  21. Trubiano JA, Dickinson M, Thursky KA et al (2017) Incidence, etiology and timing of infections following azacitidine therapy for myelodysplastic syndromes. Leuk Lymphoma 28:1–8. doi:https://doi.org/10.1080/10428194.2017.1295141

    Google Scholar 

  22. Fenaux P, Haase D, Sanz GF, Santini V, Buske C, ESMO Guidelines Working Group (2014) Myelodysplastic syndromes: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 25(Suppl e):iii57–iii69

    Article  PubMed  Google Scholar 

  23. Fenaux P (2013) Myelodysplastic syndromes: state of the art pathology, diagnosis and management. Best Pract Res Clin Haematol 26:307–308

    Article  PubMed  Google Scholar 

  24. Cogle CR, Kurtin SE, Bentley TG et al (2017) The incidence and health care resource burden of the myelodysplastic syndromes in patients in whom first-line hypomethylating agents fail. Oncologist 22:379–385

    Article  CAS  PubMed  Google Scholar 

  25. Kuendgen A, Bug G, Ottmann OG et al (2011) Treatment of poor-risk myelodysplastic syndromes and acute myeloid leukemia with a combination of 5-azacitidine and valproic acid. Clin Epigenetics 2:389–399

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Craddock C, Goardon N, Griffiths M et al (2008) 5-azacitidine in combination with valproic acid induces complete remissions in patients with advanced acute myeloid leukaemia but does not eradicate clonal leukaemic stem/progenitor cells. Blood 112:945

    Google Scholar 

  27. Issa JP, Garcia-Manero G, Huang X et al (2015) Results of phase II randomized study of low-dose decitabine with and without valproic acid in patients with myelodysplastic syndrome and acute myelogenous leukemia. Cancer 121:556–561

    Article  CAS  PubMed  Google Scholar 

  28. Prebet T, Sun Z, Ketterling RP et al (2016) Azacitidine with or without entinostat for the treatment of therapy-related myeloid neoplasms: further results of the E1905 North American Leukemia Intergroup Study. Br J Hematol 172:384–391

    Article  CAS  Google Scholar 

  29. Lund K, Cole JJ, VanderKraats ND et al (2014) DNMT inhibitors reverse a specific signature of aberrant promoter DNA methylation and associated gene silencing in AML. Genome Biol 15:406

    Article  PubMed  PubMed Central  Google Scholar 

  30. Tampe B, Steinle U, Tampe D et al (2017) Low-dose hydralazine prevents fibrosis in a murine model of acute kidney injury-to-chronic kidney disease progression. Kidney Int 91:157–176

    Article  CAS  PubMed  Google Scholar 

  31. Tampe B, Tampe D, Zeisberg EM et al (2015) Induction of Tet3-dependent epigenetic remodeling by low-dose hydralazine attenuates progression of chronic kidney disease. EBioMedicine 2:19–36

    Article  PubMed  Google Scholar 

  32. Yan H, Wang Y, Qu X et al (2017) Distinct roles for TET family proteins in regulating human erythropoiesis. Blood 129:2002–2012

    Article  CAS  PubMed  Google Scholar 

  33. Delhommeau F, Dupont S, Valle VD et al (2009) Mutation in TET2 in myeloid cancers. N Engl J Med 360:2289–2301

    Article  PubMed  Google Scholar 

  34. Smith AE, Mohamedali AM, Kulasekararaj A et al (2010) Next-generation sequencing of the TET2 gene in 355 MDS and CMML patients reveals low-abundance mutant clones with early origins, but indicates no definite prognostic value. Blood 116:3923–3932

    Article  CAS  PubMed  Google Scholar 

  35. Candelaria M, de la Cruz-Hernandez E, Taja-Chayeb L et al (2012) DNA methylation-independent reversion of gemcitabine resistance by hydralazine in cervical cancer cells. PLoS One 7:e29181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Spensberger D, Delwel R (2008) A novel interaction between the proto-oncogene Evi1 and histone methyltransferases, SUV39H1 and G9a. FEBS Lett 582:2761–2767

    Article  CAS  PubMed  Google Scholar 

  37. Detich N, Bovenzi V, Szyf M (2003) Valproate induces replication-independent active DNA demethylation. J Biol Chem 278:27586–27592

    Article  CAS  PubMed  Google Scholar 

  38. Milutinovic S, D'Alessio AC, Detich N, Szyf M (2007) Valproate induces widespread epigenetic reprogramming which involves demethylation of specific genes. Carcinogenesis 28:560–571

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Grupo Neolpharma S.A. de C.V., Mexico provided the drug for these patients. Data collection and results were analysed by the authors. The company had no role in the writing and analysis of results.

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Authors and Affiliations

  1. Division de Investigación Clínica, Instituto Nacional de Cancerología, Av. San Fernando 22, Tlalpan, 14080, México, D.F., Mexico

    Myrna Candelaria, Sebastian Burgos & Mayra Ponce

  2. Departamento de Hematología, Instituto Nacional de Cancerologia, Mexico, Mexico

    Ramiro Espinoza

  3. Unidad de Investigación Biomédica en Cáncer, Instituto de Investigaciones Biomédicas (IIB), Instituto Nacional de Cancerología (INCan), Universidad Nacional Autonóma de Mexico (UNAM), Mexico, Mexico

    Alfonso Dueñas-Gonzalez

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  1. Myrna Candelaria
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  2. Sebastian Burgos
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  3. Mayra Ponce
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  4. Ramiro Espinoza
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  5. Alfonso Dueñas-Gonzalez
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Correspondence to Myrna Candelaria.

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The authors declare that they have no conflicts of interest.

Ethics aspects

All patients were informed that the administration of this drug combination was off-label, and they signed informed consent. An IRB approved the donation of this treatment and its use in a compassionate manner.

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Candelaria, M., Burgos, S., Ponce, M. et al. Encouraging results with the compassionate use of hydralazine/valproate (TRANSKRIP™) as epigenetic treatment for myelodysplastic syndrome (MDS). Ann Hematol 96, 1825–1832 (2017). https://doi.org/10.1007/s00277-017-3103-x

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  • DOI: https://doi.org/10.1007/s00277-017-3103-x

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