AML16: Epigenetic Priming in Patients with Acute Myeloid Leukemia (CLOSED TO ACCRUAL)

Brief Summary

The overall aim of this clinical trial is to determine if epigenetic priming with DMTi prior to chemotherapy blocks is tolerable and effective in children and adolescents with newly diagnosed acute myeloid leukemia. Treatment will consist of up to five blocks of chemotherapy: Induction I, Induction II, Intensification I,  Intensification II and Intensification III. Chemotherapy blocks will be preceded by a five-day course of a DNA methyltransferase inhibitor (DMTi). Patients will be randomized to one of two single agent DMTi: azacitidine or decitabine. High-risk patients will receive a stem cell transplant in first remission. Total duration of therapy is five months.

Primary Objective

• To evaluate the tolerability of five days of epigenetic priming with azacitadine and decitabine as a single agent DMTi prior to standard AML chemotherapy blocks
• Evaluate the change in genome-wide methylation burden induced by five days of epigenetic priming and the association of post-priming genome-wide methylation burden with event-free survival among pediatric AML patients

Eligibility Criteria

Inclusion criteria include:

• Diagnosis of one of the following:
  • Acute myeloid leukemia (AML)
  • 5% to 20% marrow myeloblasts and evidence of a clonal de novo AML genetic abnormality
  • Myeloid sarcoma
  • High grade myelodysplastic syndrome (MDS) with greater than 5% blasts
  • Treatment-related myeloid neoplasms, including AML and MDS, provided their cumulative anthracycline dose has not exceeded 230 mg/m² doxorubicin equivalents
• 28 days to 21 years old
• No prior therapy, except for one dose of intrathecal therapy and the use of hydroxyurea or low-dose cytarabine
• Not pregnant

Exclusion Criteria include:

• Acute promyelocytic leukemia (APL)
• BCR-ABL1 chronic myeloid leukemia in blast crises (CML-BC)
• Juvenile myelomonocytic leukemia (JMML)
• Fanconi anemia (FA)
• Kostmann syndrome
• Shwachman syndrome
• Other bone marrow failure syndromes or low grade MDS
• Use of concomitant chemotherapy, radiation therapy or immunotherapy other than as specified in the protocol
• Use of investigational agents within 30 days of any anticancer therapy for this malignancy within 2 weeks before study entry with the exception of IT therapy, hydroxyurea or low-dose cytarabine

Study Sites

St. Jude Children’s Research Hospital, Memphis, Tennessee
Collaborating sites in and outside the U.S.

About this study

Acute myelogenous leukemia (AML) is a cancer of the bone marrow, the spongy tissue inside the large bones of the body where blood cells are made. In AML, the bone marrow makes large numbers of immature white blood cells called blasts. These blast cells crowd out the normal cells of the bone marrow. They may also invade body organs including the brain, testes, ovaries, or skin. These cancerous AML cells can sometimes form a solid tumor called a chloroma.

This study will compare the good and bad effects of giving either azacitidine OR decitabine before the usual chemotherapy regimen for childhood AML. Azacitidine and decitabine both belong to a class of drugs called “DNA methyl-transferase inhibitors or DMTi.” DMTi’s are known to alter the DNA within the genes of leukemia cells, possibly making them more sensitive to chemotherapy. Giving a DMTi before the usual chemotherapy is called “epigenetic priming” because the intent is to change the genetics of the leukemia cell by “priming” it to be more sensitive to the chemotherapy that will follow.

The U.S. Food and Drug Administration (FDA) has approved azacitidine and decitabine to treat adults with myelodysplastic syndrome. The FDA has not approved these drugs for treating children with leukemia.

Purpose of this clinical trial

The main purpose of this study is to find out if adding either azacitidine or decitabine is better, the same, or worse than the usual chemotherapy for AML. Researchers also want to know if azacitidine or decitabine is safe, and if one of the drugs is better than the other.

Eligibility overview

• Diagnosis of one of the following:
  • Acute myeloid leukemia (AML)
  • 5% to 20% marrow myeloblasts and evidence of a clonal de novo AML genetic abnormality
  • Myeloid sarcoma
  • High grade myelodysplastic syndrome (MDS) with greater than 5% blasts
  • Treatment-related myeloid neoplasms, including AML and MDS
• 28 days to 21 years old
• No prior therapy, except for one dose of intrathecal therapy and the use of hydroxyurea or low-dose cytarabine
• Not pregnant