Targeted treatments: understanding their impact on leukemia cells to improve treatment

A new study provides a better understanding of how treatments target genetic abnormalities that cause acute myeloid leukemia ... and better treat them.

For the first time in acute myeloid leukemia (AML), a team of international researchers has analyzed the genetic evolution of cancer cells from leukemia when it is treated with targeted treatment of a genetic mutation.

The aim was to understand how secondary leukemias and IDH2 mutations reacted to a targeted treatment, enasidenib, which only targets this type of mutation. It was also to understand how treated leukemias eventually escape treatment.

The study, published in Nature Medicine, is the result of international collaboration between French (Gustave Roussy and Inserm), English (MRC and Oxford University) and American (Memorial Sloan Kettering Cancer Center) researchers.

Acute leukemia

Acute myeloid leukemia (AML) is the most common and aggressive type of blood cancer in adults and is incurable in most patients.

Approximately 12 to 15% of AML patients have a mutation in the IDH2 gene, a mutation that prevents bone marrow cells from differentiating normally and becoming mature, functional blood cells that are essential for life. Instead, these immature cells accumulate in the bone marrow and blood, which they "choke".

Targeted treatment of cancer cells with IDH2 mutation

Previous research had shown that targeted treatment against the mutation of the IDH2 gene, enasidenib, promoted the maturation of cancer cells and thus restored the production of functional blood cells.

This targeted treatment is not chemotherapy and it does not attack other cells in the body. It is effective in 40% of patients with AML mutation IDH2 and are resistant to usual treatments. However, after an average period of nearly nine months, the cancer relapsed in these patients.

Study of the genealogical tree of cancer cells

Since AML is caused by DNA errors (or mutations) in the chromosomes of blood cells, the team investigated the genetic makeup of AML cells in a sample of 37 patients initially responding to enasidenib.

They found that there was a heterogeneity of genetic abnormalities in the leukemic cells of the same patient and that they could be grouped into different families (clones) sharing the same genetic mutations.

The cells belonging to the same family (same clone) come from the same ancestral cell. Understanding how clones are connected to each other is important because they provide information on how LAM has started.

A restoration of cell functions

So far it has not been known whether the mature blood cells of a patient treated with a targeted treatment came from normal cells (after all cancer cells were killed) or from leukemia cells now able to become mature.

Dr. Virginie Penard-Lacronique, research director at Gustave Roussy and co-author of the study, said: "We have provided genetic evidence that enasidenib is able to allow cancer cells to differentiate themselves in order to restore certain normal functions, even if they still contain the IDH2 mutation ".

"In this work, we show that four out of five times, mature blood cells come from bone marrow leukemia cells that may be able to differentiate by this new drug."

Relapse in the absence of associated treatment

The cancer returned to almost all patients in the clinical trial, on average after 9 months, and the team was able to show for the first time that patients stopped responding to enasidenib when certain blood cell clones developed. other mutations.

This implies that future studies with this targeted therapy should be performed in combination with other anticancer drugs to prevent the appearance of resistant leukemia cells and thus relapses.

A concept applicable to all targeted treatments

Professor Paresh Vyas, professor of hematology and head of the Oxford team, said: "The approach we have implemented can be applied to any cancer and any targeted treatment and can help understand how targeted and specific drug attacks each clone of cells in cancer and how different cell clones react.This makes it a very powerful approach to improve our understanding of how to achieve better results of a targeted cancer treatment. "

Video: Chronic Myeloid Leukemia: A Patient's Journey (November 2019).