Phase III clinical trial of CPX-351 for the treatment of myeloid leukemia in children with Down syndrome, 2018

Myeloid leukemias (ML) are blood cancers in which certain blood cells multiply uncontrollably in the bone marrow. Acute myeloid leukemia (AML) is a particularly fast-growing form in which immature blood cells displace healthy blood cells. Myelodysplastic syndrome (MDS) is a precursor to AML in which the bone marrow does not produce enough healthy blood cells.

Children with Down syndrome (trisomy 21) or mosaic Down syndrome (in which not all body cells have the extra copy of the chromosome) are at higher risk of developing ML. This is because their bone marrow more frequently produces immature blood cells that do not develop properly. AML occurs particularly often in these children. Some children with Down syndrome initially develop myelodysplastic syndrome (MDS), which can later progress to AML. An important factor in the development of the disease is the GATA-1 mutation, which is common in many children with Down syndrome. It further affects the development of blood cells and may be present from birth. This genetic change (mutation) can be detected through a genetic test of the blood or bone marrow. Depending on the course of the disease, patients are classified into the standard-risk group (SR) and the high-risk group (HR). Children with the GATA-1 mutation usually have a less aggressive form of AML and belong to the standard-risk group, while children without the GATA-1 mutation or with additional unfavorable genetic factors are classified as high-risk.

The standard treatment is based on modified chemotherapy with high-dose cytarabine, as leukemia cells in Down syndrome are particularly sensitive to it. There is currently no officially recognized new standard therapy, which is why treatment continues to be guided by the findings of the ML-DS 2006 study. In the past, children with Down syndrome were often treated with intensive AML chemotherapy that was developed for children without Down syndrome. This regimen included high doses of the cytotoxic drugs cytarabine, anthracyclines (idarubicin, mitoxantrone), and etoposide; however, it frequently led to severe side effects such as serious infections, organ damage, and heart problems. Recently, however, reducing the chemotherapy dose and shortening the treatment duration has improved tolerability and reduced side effects.

One drug that is already part of the standard treatment for high-risk AML in adult medicine is CPX-351. It contains the active ingredients daunorubicin and cytarabine in a fixed ratio of 5:1. Due to its special composition, CPX-351 releases the active ingredients more slowly, allowing them to act more effectively on leukemia cells and causing fewer side effects. It has not yet been approved for use in children outside of clinical trials.

The goal of the ML-DS 2018 study is to evaluate the efficacy and safety of CPX-351 and to improve survival rates. To this end, the children are divided into two groups based on their risk profile. Patients in both groups receive four treatment cycles. During the first two cycles, patients receive the study drug CPX-351 as an infusion through an intravenous line on several days. This is followed by two cycles of cytarabine and mitoxantrone to combat any remaining cancer cells. The high-risk group receives a higher dose of cytarabine. During treatment, the children are examined regularly to monitor side effects and the course of the disease. The results will be compared with earlier treatments—a so-called historical control arm—to determine whether CPX-351 is as effective as or more effective than the standard treatment at that time. This means that all patients participating in the study will receive the experimental treatment. Follow-up as part of the study will continue for 5 years.

Children with Down syndrome (trisomy 21) or mosaic Down syndrome who have acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) are eligible to participate in the study. They must be older than 6 months and no older than 4 years (regardless of a GATA-1 mutation) or between 4 and 6 years of age with a GATA-1 mutation. Previous intensive chemotherapy, biological therapy, or radiation therapy that lasted longer than 14 days or took place less than 4 weeks before the start of study treatment excludes participants from enrollment.