An international, open-label, multicenter clinical trial for the treatment of acute myeloid leukemia in children and adolescents

Acute leukemias are rapidly progressing, aggressive forms of cancer that arise from immature white blood cells or bone marrow cells (leukocytes) and usually spread very quickly. The malignant leukemia cells develop in the bone marrow and displace the healthy bone marrow, resulting in an insufficient production of functional blood cells. In cases of this disease, patients frequently experience infections, bleeding, reduced performance, and shortness of breath. In acute myeloid leukemia (AML), the precursors of the so-called myeloid cell line of leukocytes—from which red blood cells, for example, are also formed—are altered. Overall, AML is a rare disease; however, it is the second most common type of blood cancer (leukemia) in children.

Children with acute myeloid leukemia (AML) receive intensive chemotherapy in several phases. Various chemotherapy drugs, such as daunorubicin, cytarabine, and etoposide, are used. Additionally, various chemotherapy drugs are administered directly into the cerebrospinal fluid (intrathecal). They act as cytotoxic agents and thereby destroy both cancer cells and healthy cells. This can result in severe side effects, such as damage to various organs and an increased risk of infection. The new drug CPX-351 (Vyxeos) also contains the two cytotoxic agents cytarabine and daunorubicin, but they are encapsulated in a lipid coating. This is intended to reduce side effects on organs while maintaining the same efficacy against leukemia cells. The drug is already approved for the treatment of AML in adults.

If the disease recurs during or after therapy, further treatment is necessary. For this, chemotherapy drugs are used again, but at higher doses. In adult medicine, the drug gemtuzumab ozogamicin, among others, is already approved for this purpose. This is an antibody-drug conjugate that specifically binds to the CD33 surface protein on cancer cells. However, this protein is not present on all tumor cells and is therefore used primarily in patients who have a specific genetic mutation (CBF mutation), as tumor cells with this mutation express particularly high levels of CD33 protein.

For high-risk patients or following a relapse, a stem cell transplant from another person (allogeneic) is often necessary to achieve a cure. In this procedure, the diseased bone marrow is replaced with healthy donor bone marrow. Here, too, it should be assessed whether it is possible to prepare for the transplant (known as conditioning) using a different combination of drugs with fewer side effects but the same efficacy. To ensure that the new bone marrow can be accepted, the old bone marrow is destroyed through what is known as conditioning chemotherapy. The standard treatment involves the drug busulfan in combination with other agents. These drugs suppress the immune system and kill the remaining leukemia cells, but they can also cause severe side effects. Treosulfan can also be used instead of busulfan. The drug is already approved for use in children and has shown in studies that it has fewer side effects while maintaining the same level of efficacy. However, these results still need to be confirmed in further studies.

The goal of this Phase 3 study is to improve the chances of cure for children with AML and reduce the long-term damage caused by treatment through the use of new or alternative medications. To this end, data on the safety and efficacy of various medications at different stages of the disease will be collected. Patients will be assigned to one of three study arms, depending on the stage of their disease. Arm 1 will include patients with untreated AML. Here, patients will be randomly assigned to two groups. Study group 1 receives the new drug CPX-351 (Vyxeos) and standard chemotherapy, while control group 1 receives the current standard chemotherapy. Arm 2 includes patients who have experienced a first recurrence of AML (first relapse) or in whom initial treatment was ineffective (primary refractory). They are tested for a CBF mutation and divided into two groups based on their mutation status. Patients with a CBF mutation (Control Group 2) receive standard therapy; all others (Study Group 2) receive the drug gemtuzumab ozogamicin in addition to standard therapy. Study arm 3 includes patients who require a stem cell transplant. They are also randomly assigned to two groups. Study group 3 receives treosulfan as part of their conditioning therapy, while control group 3 receives the conventional drug busulfan. The study is open-label, meaning that both the medical staff and the patients know which medications are being administered. The duration of treatment varies across the different groups and depends, among other factors, on treatment success and side effects.

Children and adolescents up to age 21 who have AML are eligible to participate in the study. Only patients who received their first course of chemotherapy for their AML before their 18th birthday—or who will receive it as part of the study—are eligible to participate. Patients with trisomy 21, acute promyelocytic leukemia (APL), and AML with the 15;17 translocation (t(15;17)) are excluded from participating in the study.