The role of epigenetic therapy in the treatment of childhood acute myeloid leukemia

The treatment results of children with acute myeloid leukemia (AML) still remain unsatisfactory. The standard chemotherapy allows achieving complete remission in 91–96% of patients, but the event-free (EFS) and overall (OS) survival rates are still not high enough, the main cause of treatment failure in children with AML is relapse of the disease. DNA methylation and histone modification are major epigenetic changes in AML, leading to silencing of tumor suppressor genes. Research of the epigenetic control of gene expression in AML through histone modification and DNA demethylation promotes better understanding of the biology of blasts.

The aim of our study: to prove the effectiveness of the NII DOG AML 2012 protocol based on the combination of standard chemotherapy and epigenetic therapy. The study was approved by the Independent Ethics Committee and the Scientific Council of the N.N. Blokhin NMRC of Oncology of Ministry of Healthcare of the Russian Federation. From 01.01.2013 to 31.05.2019, the following patients were enrolled in the study: 35 patients who were receiving treatment according to the NII DOG AML 2012 protocol and 52 patients who were receiving treatment according to the AML-BFM 2004 protocol. Between two groups, there was no significant difference in sex, age, and distribution by risk groups. The high-risk and intermediate-risk patients received 5 courses of chemotherapy (AIE, HAM, AI, hAM, HAE) and the standard-risk patients received 4 courses of chemotherapy (AIE, AI, hAM, HAE). Epigenetic therapy according to the NII DOG AML 2012 protocol consisted of valproic acid (weeks 1–78), all-trans-retinoic acid (days 1–43 and then days 1–14 of each subsequent chemotherapy course) and decitabine 20 mg/m² which was given within a therapeutic window in 5 patients and 26 patients received it on days 16–20 from the beginning of treatment. Six patients received 5-azacitidine instead of decitabine. There was no toxicity in 5 patients who received decitabine within a therapeutic window: one patient developed relapse (13 months) and one patient died of severe infection after induction therapy on day 17, three patients are still alive in complete remission (67, 70, and 72 months), with two of them having received haploidentical hematopoietic stem cell transplantation. All the patients who received decitabine on days 16–20 achieved complete remission after induction therapy (2 patients of them did not respond to AIE treatment and achieved remission only after decitabine treatment). Among the patients who were treated with chemotherapy only, complete remission was achieved in 82.6% (p = 0.04). In the patients treated according to the NII DOG AML 2012 protocol, the 5-year EFS and OS was 69.1 ± 9.8%, and 73.5 ± 9.4%, respectively, vs 54.0 ± 7.3% (p = 0.2) and 69.2 ± 6.4% (p = 0.58) in the patients treated with chemotherapy only. The five-year EFS and cumulative incidence of relapse (CIR) of the high-risk patients treated according to the NII DOG AML 2012 and AML-BFM 2004 protocol were 77.8 ± 13.4% vs 50.0 ± 8.6% (p = 0.044) and 15.2 ± 10% vs 42.5 ± 9.2% (p = 0.056), respectively. None of the patients treated according to the NII DOG AML 2012 protocol underwent allogeneic hematopoietic stem cell transplantation (HSCT) during the first remission. After excluding from the analysis 6 patients who received allogeneic HSCT during the first remission and were treated according to the AML-BFM 2004 protocol, the EFS and CIR rates of the high-risk patients were 46.4 ± 9.4% (p = 0.02) and 47.4 ± 9.5% (p = 0.029), respectively. All the six patients who received 5-azacitidine instead of decitabine died (one patient died during induction therapy and 5 patients died of AML progression) and further study of this arm of the protocol was closed. Thus, the addition of epigenetic therapy to standard chemotherapy in pediatric patients with AML reduced the CIR, increased the number of complete remissions and the overall survival compared with the patients treated with chemotherapy only. The high-risk patients treated according to the NII DOG AML 2012 protocol achieved higher EFS and lower CIR rates compared with the patients who received no demethylating agents and underwent no allogeneic HSCT. Probably, epigenetic therapy may allow patients to avoid allogeneic HSCT during the first complete remission. According to our study results, decitabine has shown to be more effective than 5-azacitidine. Decitabine should be given after the first course of induction therapy during the period of aplasia.