Targeted therapies for childhood ALL and AML

This article reviewed targeted therapies under investigation for childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).

Treatment options have improved survival rates in childhood leukemia. However, up to 20% of ALL patients will relapse. Relapse rates are also high in AML. New treatments are therefore needed.

Targeted therapies are those that target specific proteins and molecules involved in cancer growth. They can also stimulate the immune system to attack cancer cells. Targeted therapies are currently the focus of much research in childhood ALL and AML.

This article reviewed the treatments under investigation in AML and ALL.

ALL

Some cases of ALL are caused by a genetic abnormality known as the Philadelphia chromosome. Imatinib (Gleevac) is a therapy that targets tyrosine kinase, a protein associated with to the Philadelphia chromosome. Combining imatinib with chemotherapy improved 3-year event-free survival (time from treatment until an event such as progression, death, or treatment discontinuation) to 88%. This was more than double the rate without imatinib. Similar treatments (dasatinib, nilotinib, and ponatinib) are under investigation.

Proteasome inhibitors interfere with cancer growth. Bortezomib (Velcade) is a proteasome inhibitor tested in ALL. A 73% response rate was noted in a study of 22 relapsed childhood ALL patients. Another study reported a 68% complete remission (CR; no sign of disease) rate in 61 patients.

Antibody therapies bind to antigens on the surface of cancer cells. Epratuzumab binds to the antigen CD22, found in 96% of B-cell ALL patients. Adult studies have shown improved CR rates. Inotuzumab ozogamicin (IO) also binds to CD22, but is combined with calicheamicin, an antibiotic that can cause leukemia cell death.  IO has been shown to be effective at inducing CR in both adults and children. Blinatumomab (Blincyto) targets CD19/CD3. 61% of patients were relapse-free after an average of 33 months in a small study.

Chimeric antigen receptor-modified T-cells are immune cells (the T-cells) that are removed from the blood.  The T-cells are then genetically engineered (modified) in a laboratory to produce CAR. CAR is a protein that helps the T-cells recognize ALL cells as something to attack. After the T-cells are modified, they are CAR-T cells. The CAR-T cells are reintroduced into the patient and will then attack ALL cells. This treatment led to a CR in 82% of 17 patients after 1 month.

AML

Roughly 20% to 25% of childhood AML is associated with a mutation in the FLT3-ITD gene. This mutation can lead to an increased risk of relapse. Treatments that block FLT3-ITD, such as sorafenib (Nexavar), have been shown to improve outcomes. Other FLT3-ITD inhibitors under investigation in childhood AML include lestaurtinib, quizartinib, and midostaurin.

Proteasome inhibitors interfere with cancer growth. Bortezomib (Velcade) is a proteasome inhibitor under investigation in AML. Adult trials have determined that it can be safely combined with chemotherapy.

Antibody therapies bind to antigens on the surface of cancer cells. Gemtuzumab (GO, Mylotarg) is an antibody treatment that binds to the antigen CD33. CD33 is present in 88% of childhood AML leukemia cells. GO is combined with calicheamicin, an antibiotic that can cause leukemia cell death. This treatment can increase 3-year event free survival (time from treatment until an event such as progression or death) but has been associated with side effects. It is not currently available in the United States, except with special permission.

This study reported on current and future targeted treatments for childhood ALL and AML.