Inhibitors of histon deacetylase (HDAC) and DNA methyltransferase in treatment children with acute myeloid leukemia, effectiveness and place
https://doi.org/10.17650/2311-1267-2016-3-4-48-54
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Abstract
The results of treatment children with acute myeloid leukemia (AML) are not satisfied yet. The standard chemotherapy allows achieve complete remission in 92–96 % of patients, but disease free survival (DFS) and event free survival (EFS) are not good yet.
In a new study – NII DOG AML 2012 – the specific aim was to explore effectiveness demethylating drug (Decitabine) and inhibitors of histon deacetylase (HDAC) to find the place in standard chemotherapy.
From 01.2013 to 09.2016 26 patients were enrolled into NII DOG AML 2012 study. The average was 6.5 ± 1.24 years (6 mo – 16 years): 15 males and 11 females, standard (SR) – 2 (7.7 %), intermediate (IR) – 7 (26.9 %) and high (HR) – 17 (65.4 %) risk groups.
Chemotherapy consisted on 5 courses for HR and IR (AIE, HAM, AI, hAM, HAE) and 4 courses for SR (AIE, HAM, hAM, HAE). Epigenetic therapy consisted of Valproic acid (VA) weeks 1–78, All Trans Retinoic Acid (ATRA) 1–43 days and from the day one to day 14 of the every course chemotherapy and Decitabine in “window” regime before induction (5 pts) and on day 16 after beginning of induction.
Decitabine was given as a demethylating drug 20 mg/m2 for 5 days in “window” regime before induction (AIE). There were no any toxicity and we did not check decrease of blasts in BM and peripheral blood after Decitobine, one of them developed relapse and one died from severe infection, 3 pts are alive, but two of them underwent haploidentical HSCT. Decitobine was moved on the day 16. Now, 21 pts got this therapy, all of them achieved CR after AIE with VA, ATRA and Decitobine, two pts did not respond to induction and achieved CR just after Decitobine. Three years DFS and EFS were the same – 67.9 ± 12 % with median follow up 28.1 ± 3.1 mo, OS – 81.6 ± 9.6 % with median follow up 31.0 ± 2.6 mo. None of the patients underwent HSCT.
Thus, epigenetic therapy increases rate of CR, DFS and EFS in children with AML. Demethylating drug has to be used during aplasia and HDAC inhibitors – during the whole chemotherapy program.
About the Authors
A. V. PopaRussian Federation
23 Kashirskoe Sh., Moscow, 115478
V. S. Nemirovchenko
Russian Federation
23 Kashirskoe Sh., Moscow, 115478
E. V. Fleyshman
Russian Federation
24 Kashirskoe Sh., Moscow, 115478
O. I. Sokova
Russian Federation
24 Kashirskoe Sh., Moscow, 115478
N. N. Subbotina
Russian Federation
23 Kashirskoe Sh., Moscow, 115478
I. N. Serebryakova
Russian Federation
23 Kashirskoe Sh., Moscow, 115478
L. J. Grivtsova
Russian Federation
23 Kashirskoe Sh., Moscow, 115478
G. L. Mentkevich
Russian Federation
23 Kashirskoe Sh., Moscow, 115478
References
1. Swerdlow S.H., Campo E., Harris N.L. et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008.
2. Balgobind B.V., Hollink I.H., ArentsenPeters S.T. et al. Integrative analysis of type-I and type-II aberrations underscores the genetic heterogeneity of pediatric acute myeloid leukemia. Haematologica 2011;96(10):1478-87.
3. de Rooij J.D., Zwaan C.M., van den HeuvelEibrink M. Pediatric AML: From Biology to Clinical Management. J Clin Med 2015;4(1):127-49.
4. Valerio D.G., Katsman-Kuipers J.E., Jansen J.H. et al. Mapping epigenetic regulator gene mutations in cytogenetically normal pediatric acute myeloid leukemia. Haematologica 2014;99(8):e130-2.
5. Creutzig U., Zimmermann M., Bourquin J.P. et al. Randomized trial comparing liposomal daunorubicin with idarubicin as induction for pediatric acute myeloid leukemia: Results from Study AMLBFM 2004. Blood 2013;122(1):37-43.
6. Cooper T.M., Franklin J., Gerbing R.B. et al. AAML03P1, a pilot study of the safety of gemtuzumab ozogamicin in combination with chemotherapy for newly diagnosed childhood acute myeloid leukemia: A report from the Children’s Oncology Group. Cancer 2012;118(3):761-9.
7. Gibson B.E., Webb D.K., Howman A.J. et al.; United Kingdom Childhood Leukaemia Working Group; the Dutch Childhood Oncology Group. Results of a randomized trial in children with Acute Myeloid Leukaemia: Medical research council AML12 trial. Br J Haematol 2011;155(3):366-76.
8. Popa A.V., Gorokhova E.V., Fleishman E.V. i dr. Epigeneticheskaya terapiya - vazhnaya sostavlyayushchaya v lechenii detei, bol'nykh ostrym mieloidnym leikozom. Klinicheskaya onkogematologiya 2011;4(1):20-6. [Popa A.V., Gorohova E.V., Fleyshman E.V. et al. Epigenetic therapy is an important component in treating children with acute myeloid leukemia. Klinicheskaya onkogematologiya = Clinical Oncohematology 2011;4(1):20-6. (In Russ.)].
9. Nemirovchenko N.V. Rol' val'proevoi i polnost'yu trans-retinoevoi kislot v lechenii detei s ostrym mieloidnym leikozom. Avtoref. dis. ... kand. med. nauk. M., 2014. [Nemirovchenko N.V. The role of valproic acid and all-trans-retinoic acid in the treatment of children with acute myeloid leukemia. Dissert. PhD. M., 2014. (In Russ.)].
10. Moore A.S., Kearns P.R., Knapper S. et al. Novel therapies for children with acute myeloid leukaemia. Leukemia 2013;27(7):1451-60.
11. Meshinchi S., Alonzo T.A., Stirewalt D.L. et al. Clinical implications of FLT3 mutations in pediatric AML. Blood 2006;108(12):3654-61.
12. Sallmyr A., Fan J., Datta K. et al. Internal tandem duplication of FLT3 (FLT3/ITD) induces increased ROS production, DNA damage, and misrepair: implications for poor prognosis in AML. Blood 2008;111(6):3173-82.
13. Gu T.L., Nardone J., Wang Y. et al. Survey of activated FLT3 signaling in leukemia. PLoS One 2011;6(4):e19169.
14. Pollard J.A., Chang B.H., Cooper T.M. et al. Sorafenib treatment following hematopoietic stem cell transplant in pediatric FLT3/ITD+ AML. Blood 2013;122(21):3969.
15. Trus M.R., Yang L., Suarez Saiz F. et al. The histone deacetylase inhibitor valproic acid alters sensitivity towards all trans retinoic acid in acute myeloblastic leukemia cells. Leukemia 2005;19(7):1161-8.
Review
For citations:
Popa A.V., Nemirovchenko V.S., Fleyshman E.V., Sokova O.I., Subbotina N.N., Serebryakova I.N., Grivtsova L.J., Mentkevich G.L. Inhibitors of histon deacetylase (HDAC) and DNA methyltransferase in treatment children with acute myeloid leukemia, effectiveness and place. Russian Journal of Pediatric Hematology and Oncology. 2016;3(4):48-54. (In Russ.) https://doi.org/10.17650/2311-1267-2016-3-4-48-54
ISSN 2413-5496 (Online)