High Risk Myelodysplasia Treated by Azacytidine : Genetic and Epigenetic (MYRAGE)

NCT03217903 | Unknown

• 1 other identifier: MYRAGE
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 2

Brief Summary

Myelodysplastic syndromes (MDS) are the most frequent myeloid neoplasms in Western Countries.They mainly affect patients aged 65 years or older. This is a very heterogenous group of diseases, which prognosis is evaluated with International Prognosis Scoring System. High risk MDS present with high frequency of transformation into acute myeloid leukemia. Treatment of high risk MDS often is based on hypomethylating agents, such as 5'-azacytidine (Azacytidine), with a complete response in approximativel 20% of cases.. This treatment is based on 4-week cycles, with daily injection during the first week and rest during the 3 next weeks of the cycle. Azacytidine efficacy is commonly evaluated with clinical and biological parameters determined by the International Working Group 2006. These parameters are usually evaluated after at least 6 cycles of treatments. There is a response with Azacytidine treatment in 60% of cases, including 40% of partial responses and 20% of complete responses. In 40% of patients, there is no response, which means that the disases is stable or in progression under therapy. In this regard, early evaluation of treatment response is an issue. We want to improve our knowledge about early response criteria in Azacytidine-treated high-risk MDS, focusing on SMD with excess blasts, which represent 30 to 40% of total MDS. Then, the investigator team want to compare DNA methylation profile at diagnosis and after 3 cycles of Azacytidine treatment. Main objective : Identify DNA methylation profiles related to response to Azacytidine therapy, after only 3 cycles of treatment, in high risk MDS with excess blasts. Secondary objective : Identify at diagnosis DNA methylation profiles that are predicitive of response to Azacytidin, in high risk MDS with excess blasts.

Conditions

High-risk Myelodysplastic Syndromes With Excess Blasts

Keywords

Myelodysplastic syndromes

Outcome Measures

Primary Outcomes (2)

• Methylation level of the Differentially Methylated Regions (DMR)

  3 months (after 3 cycles of treatment)

• Overall response by IWG 2006 response criteria (complete remission / partial remission / non response)

  At the treatment response assessment (After 6-12 cycles of treatment up to 52 weeks)

Secondary Outcomes (5)

• Methylation level of the Differentially Methylated Regions (DMR)

  At diagnosis

• Cytogenetic response by IWG 2006 response criteria (major / minor / no response)

  At the treatment response assessment (After 6-12 cycles of treatment up to 52 weeks)

• Hematologic improvement by IWG 2006 response criteria (major / minor / no response)

  At the treatment response assessment (After 6-12 cycles of treatment up to 52 weeks)

• Transfusion independence (yes/no)

  At the treatment response assessment (After 6-12 cycles of treatment up to 52 weeks)

• General condition improvement (yes/no)

  At the treatment response assessment (After 6-12 cycles of treatment up to 52 weeks)

Study Arms (1)

Patients with High-risk MDS With Excess Blasts

EXPERIMENTAL

Diagnostic Test: Myelogram

Interventions

Myelogram DIAGNOSTIC_TEST

Bone marrow aspiration after 3 cycles of Azacytidine treatment

Patients with High-risk MDS With Excess Blasts

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• patient benefiting from social welfcare
• patient followed at the University Hospital of Nancy
• patient aged 18 years or older
• No personal history of myelodysplastic syndrome
• clinical exam adapted to research
• one or more blood cytopenia
• patient benefiting from social welfcare
• patient followed at the University Hospital of Nancy
• patient aged 18 years or older
• definitive diagnosis of high risk myelodysplastic syndrome with excess blasts
• eligibility to an Azacytidine therapy as first-line treatment

You may not qualify if:

• personal history or current other cancer
• immediate acute myeloid leukemia
• personal history of demethylation treatment
• pregnant or breast feeding women
• life-theatening condition
• guardianship
• imprisoned patients

Sponsors & Collaborators

• Central Hospital, Nancy, France: lead
• Inserm U954 - N-GERE (Nutrition, Genetics and Exposition to Environmental Risk): collaborator

Study Sites (2)

CHRU de Nancy

Nancy, 54035, France

NOT YET RECRUITING

BROSEUS

Vandœuvre-lès-Nancy, France

RECRUITING

Related Publications (13)

• Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, Bloomfield CD, Cazzola M, Vardiman JW. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016 May 19;127(20):2391-405. doi: 10.1182/blood-2016-03-643544. Epub 2016 Apr 11.

  PMID: 27069254 RESULT

• Bejar R, Stevenson K, Abdel-Wahab O, Galili N, Nilsson B, Garcia-Manero G, Kantarjian H, Raza A, Levine RL, Neuberg D, Ebert BL. Clinical effect of point mutations in myelodysplastic syndromes. N Engl J Med. 2011 Jun 30;364(26):2496-506. doi: 10.1056/NEJMoa1013343.

  PMID: 21714648 RESULT

• Chen G, Broseus J, Hergalant S, Donnart A, Chevalier C, Bolanos-Jimenez F, Gueant JL, Houlgatte R. Identification of master genes involved in liver key functions through transcriptomics and epigenomics of methyl donor deficiency in rat: relevance to nonalcoholic liver disease. Mol Nutr Food Res. 2015 Feb;59(2):293-302. doi: 10.1002/mnfr.201400483. Epub 2014 Dec 9.

  PMID: 25380481 RESULT

• Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, Pinto A, Beran M, de Witte TM, Stone RM, Mittelman M, Sanz GF, Gore SD, Schiffer CA, Kantarjian H. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006 Jul 15;108(2):419-25. doi: 10.1182/blood-2005-10-4149. Epub 2006 Apr 11.

  PMID: 16609072 RESULT

• Delhommeau F, Dupont S, Della Valle V, James C, Trannoy S, Masse A, Kosmider O, Le Couedic JP, Robert F, Alberdi A, Lecluse Y, Plo I, Dreyfus FJ, Marzac C, Casadevall N, Lacombe C, Romana SP, Dessen P, Soulier J, Viguie F, Fontenay M, Vainchenker W, Bernard OA. Mutation in TET2 in myeloid cancers. N Engl J Med. 2009 May 28;360(22):2289-301. doi: 10.1056/NEJMoa0810069.

  PMID: 19474426 RESULT

• Fandy TE, Herman JG, Kerns P, Jiemjit A, Sugar EA, Choi SH, Yang AS, Aucott T, Dauses T, Odchimar-Reissig R, Licht J, McConnell MJ, Nasrallah C, Kim MK, Zhang W, Sun Y, Murgo A, Espinoza-Delgado I, Oteiza K, Owoeye I, Silverman LR, Gore SD, Carraway HE. Early epigenetic changes and DNA damage do not predict clinical response in an overlapping schedule of 5-azacytidine and entinostat in patients with myeloid malignancies. Blood. 2009 Sep 24;114(13):2764-73. doi: 10.1182/blood-2009-02-203547. Epub 2009 Jun 22.

  PMID: 19546476 RESULT

• Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Sole F, Bennett JM, Bowen D, Fenaux P, Dreyfus F, Kantarjian H, Kuendgen A, Levis A, Malcovati L, Cazzola M, Cermak J, Fonatsch C, Le Beau MM, Slovak ML, Krieger O, Luebbert M, Maciejewski J, Magalhaes SM, Miyazaki Y, Pfeilstocker M, Sekeres M, Sperr WR, Stauder R, Tauro S, Valent P, Vallespi T, van de Loosdrecht AA, Germing U, Haase D. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012 Sep 20;120(12):2454-65. doi: 10.1182/blood-2012-03-420489. Epub 2012 Jun 27.

  PMID: 22740453 RESULT

• Itzykson R, Kosmider O, Cluzeau T, Mansat-De Mas V, Dreyfus F, Beyne-Rauzy O, Quesnel B, Vey N, Gelsi-Boyer V, Raynaud S, Preudhomme C, Ades L, Fenaux P, Fontenay M; Groupe Francophone des Myelodysplasies (GFM). Impact of TET2 mutations on response rate to azacitidine in myelodysplastic syndromes and low blast count acute myeloid leukemias. Leukemia. 2011 Jul;25(7):1147-52. doi: 10.1038/leu.2011.71. Epub 2011 Apr 15.

  PMID: 21494260 RESULT

• Meldi K, Qin T, Buchi F, Droin N, Sotzen J, Micol JB, Selimoglu-Buet D, Masala E, Allione B, Gioia D, Poloni A, Lunghi M, Solary E, Abdel-Wahab O, Santini V, Figueroa ME. Specific molecular signatures predict decitabine response in chronic myelomonocytic leukemia. J Clin Invest. 2015 May;125(5):1857-72. doi: 10.1172/JCI78752. Epub 2015 Mar 30.

  PMID: 25822018 RESULT

• Nazha A, Narkhede M, Radivoyevitch T, Seastone DJ, Patel BJ, Gerds AT, Mukherjee S, Kalaycio M, Advani A, Przychodzen B, Carraway HE, Maciejewski JP, Sekeres MA. Incorporation of molecular data into the Revised International Prognostic Scoring System in treated patients with myelodysplastic syndromes. Leukemia. 2016 Nov;30(11):2214-2220. doi: 10.1038/leu.2016.138. Epub 2016 May 20.

  PMID: 27311933 RESULT

• Rasmussen KD, Jia G, Johansen JV, Pedersen MT, Rapin N, Bagger FO, Porse BT, Bernard OA, Christensen J, Helin K. Loss of TET2 in hematopoietic cells leads to DNA hypermethylation of active enhancers and induction of leukemogenesis. Genes Dev. 2015 May 1;29(9):910-22. doi: 10.1101/gad.260174.115. Epub 2015 Apr 17.

  PMID: 25886910 RESULT

• Santini V, Melnick A, Maciejewski JP, Duprez E, Nervi C, Cocco L, Ford KG, Mufti G. Epigenetics in focus: pathogenesis of myelodysplastic syndromes and the role of hypomethylating agents. Crit Rev Oncol Hematol. 2013 Nov;88(2):231-45. doi: 10.1016/j.critrevonc.2013.06.004. Epub 2013 Jul 7.

  PMID: 23838480 RESULT

• Sperling AS, Gibson CJ, Ebert BL. The genetics of myelodysplastic syndrome: from clonal haematopoiesis to secondary leukaemia. Nat Rev Cancer. 2017 Jan;17(1):5-19. doi: 10.1038/nrc.2016.112. Epub 2016 Nov 11.

  PMID: 27834397 RESULT

MeSH Terms

Conditions

Myelodysplastic Syndromes

Interventions

Myelography

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Neuroradiography; Neuroimaging; Diagnostic Imaging; Diagnostic Techniques and Procedures; Diagnosis; Radiography; Diagnostic Techniques, Neurological; Investigative Techniques

Central Study Contacts

Julien BROSÉUS, MD, PhD

CONTACT

(+ 33) 3 83 15 49 14; j.broseus@chru-nancy.fr

Aurore PERROT, MD, PhD

CONTACT

(+33) 3 83 15 51 66; au.perrot@chru-nancy.fr

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: SCREENING
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 3, 2017
• First Posted: July 14, 2017
• Study Start: October 12, 2017
• Primary Completion: January 1, 2022
• Study Completion: January 1, 2022
• Last Updated: August 6, 2019

Record last verified: 2019-08

Locations

FR (2)