Precision Medicine in Childhood Leukemia: MRD Testing and Targeted Therapies

Jump To Section

• Precision vs. Personalized Medicine
• Minimal Residual Disease (MRD)
• MRD-Guided Treatment Decisions
• Targeted Therapy Examples
• Future of Precision Medicine
• Reducing Treatment Toxicity

Precision vs. Personalized Medicine

Dr. Shai Izraeli, MD, clarifies a critical distinction in modern oncology terminology, preferring "precision medicine" over the more commonly used "personalized medicine." He argues that all medical treatment has always been personalized to the individual patient, a practice dating back to ancient healers. The true revolution, according to Dr. Izraeli, lies in the newfound precision offered by genomic technology, which allows oncologists to tailor childhood leukemia therapy with unprecedented accuracy based on the specific biological characteristics of a patient's cancer.

Minimal Residual Disease (MRD)

Minimal residual disease refers to the small number of leukemia cells that remain in the bone marrow after treatment has induced remission, a state where cancer is no longer detectable under a microscope. Dr. Shai Izraeli, MD, explains that these persistent cells are the reason leukemia relapses if therapy is stopped too early. The advent of next-generation sequencing (NGS) has created a paradigm shift, enabling clinicians to detect a single cancer cell among 10,000 to one million normal cells. This incredibly sensitive measurement of MRD is a cornerstone of precision medicine in pediatric oncology.

MRD-Guided Treatment Decisions

The quantification of minimal residual disease directly informs critical treatment decisions for a child with leukemia. Dr. Shai Izraeli, MD, details how this works: a patient who shows no detectable MRD after initial chemotherapy has responded fantastically and may be a candidate for less intensive, less toxic subsequent therapy. Conversely, if testing reveals a significant level of MRD—for example, one leukemic cell per 1,000 normal cells—it signals a need for more aggressive treatment. Persistently high MRD levels after intensified therapy may indicate that a patient requires a bone marrow transplant, a highly toxic procedure now reserved for the highest-risk cases.

Targeted Therapy Examples

Precision medicine also encompasses developing drugs that specifically target the genetic abnormalities driving leukemia. Dr. Shai Izraeli, MD, highlights the BCR-ABL genetic abnormality, which is targeted by medications like imatinib (Gleevec). Before this targeted therapy, acute lymphoblastic leukemia (ALL) with BCR-ABL was almost universally fatal, requiring a bone marrow transplant for any chance of survival. Now, combining imatinib with chemotherapy cures approximately 60% of these children without a transplant. Dr. Izraeli also mentions Philadelphia-like leukemia, another subtype found in children with Down syndrome, where emerging targeted therapies are showing promise.

Future of Precision Medicine

Dr. Shai Izraeli, MD, believes we are at the very beginning of the precision medicine era for curing childhood leukemia. He anticipates that technological advances will soon allow for the detection of a single cancer cell in a million normal cells, further refining risk stratification. The continued discovery of new targetable genetic lesions and the development of corresponding drugs, such as FLT3 inhibitors and antibody-based therapies, promise to push cure rates even higher while continually de-escalating the use of toxic conventional chemotherapy.

Reducing Treatment Toxicity

A primary goal of precision medicine in pediatric leukemia is to reduce the short- and long-term toxicity of treatment. As Dr. Shai Izraeli, MD, explains, using MRD to identify patients who can be cured with less therapy directly minimizes exposure to dangerous chemotherapeutic agents. This approach spares children from severe side effects, organ damage, and secondary cancers later in life. Furthermore, the success of targeted therapies in replacing or reducing the need for bone marrow transplants eliminates the significant morbidity and mortality associated with that procedure, marking a monumental step forward in patient care.

Full Transcript

Dr. Anton Titov, MD: Personalized medicine or precision medicine? Top pediatric hematologist oncologist explains the difference in cutting-edge leukemia treatment. How to maximize leukemia treatment efficiency and minimize toxicity and side-effects? We live in the precision medicine era of cancer treatment.

Dr. Anton Titov, MD: You co-authored several important reviews in precision medicine treatment of pediatric leukemia. It is also called personalized medicine therapy for child leukemia. Could you please tell us what is new in precision medicine treatment of pediatric leukemia?

Dr. Shai Izraeli, MD: Precision medicine targeted cancer therapy is already happening now. Perhaps we can expect leukemia cure in the next 5-10 years? Precision medicine is very important.

Dr. Shai Izraeli, MD: First of all, thank you for using the term "precision medicine." Because the most common term that is being used is "personalized medicine." I don't like this term so much. Every treatment is personalized!

Exactly! I don't like the "personalized medicine" term so much. Because I think that from the time of Hippocrates, I'm Jewish, so from the time of the Rambam. Rambam was a doctor. He was one of the big Jewish scholars in Egypt many years ago. Treatment in medicine was always personalized. It is always personalized.

But now pediatric leukemia cancer therapy is more precise. In child leukemia there are two aspects to precision medicine. One aspect that is already in use. This is very important!

We have now the technological genomic tools to identify and quantify the residual cancer cells. Let me explain it. When leukemia is diagnosed, it's not a big deal. Everybody can diagnose leukemia. You have 100,000 cells, you look at the microscope. You see many leukemic cells.

But then we treat leukemia with chemotherapy. After treatment we don't see the leukemic cells in the microscope anymore. But we know they exist.

Dr. Anton Titov, MD: How do we know leukemic cells exist?

Dr. Shai Izraeli, MD: Because after a month of child leukemia cancer therapy we can stop therapy. Then leukemia will return in every child with leukemia. Cancer will return in every adult with leukemia. We need long-term therapy.

We have now very precise tools. They can identify now one leukemic cell out of 10,000 normal cells. Next year we will be able to find just one cancer cell over a million normal cells. We will use technologies that are called next generation sequencing.

Dr. Anton Titov, MD: Why is this important?

Dr. Shai Izraeli, MD: It's important because we learned that we can adjust leukemia therapy to this measurable few cancer cells that remain. It is called minimal residual disease. These are leukemia cancer cells that remain after cancer therapy.

We measure the amount of these residual leukemic disease after one month. We may discover that we don't find the leukemia cells at all. Our diagnostic tests have a sensitivity of one to ten thousand cells, one to 100,000 or one to 1 million cells.

But this doesn't mean that there are no residual leukemic cells somewhere in the body. It means that the patient responded fantastically to leukemia therapy. We can now give less chemotherapy.

Why is it important to give less chemotherapy? Because of toxicity, of course. Less cancer therapy is less dangerous. On the other hand, in the same patient we may discover that there are residual cancer cells after leukemia therapy.

It could be one leukemia cell out of 1,000 normal cells. There are no cancer cells under the microscope. But by these genomic sequencing methods, we know that we need to give more leukemia therapy to a child with leukemia.

After additional 2 or 3 months of leukemia therapy we may still discover that one of every 1,000 cells still is a leukemic cell. Then we need to go on to bone marrow transplant. This is a very toxic therapy. This is one way of precision medicine.

We can adjust cancer therapy to the residual leukemic cells. We can identify remaining leukemic cells by the genomic Next Generation Sequencing methods [NGS].

Second type of precision medicine is developing cancer medications that precisely target the abnormal changes. Targeted leukemia treatment medications target abnormal genomic change in the leukemic cell.

A fantastic example is chromosomal abnormality that is called BCR ABL. It was discovered many years ago. I don't know why BCR-ABL discovery did not get the Nobel Prize. One of the discoverers of the BCR-ABL molecular abnormality was Professor Eli Canaani. He works at Weitzmann Institute, here in Israel.

A specific leukemia cancer medication was developed. It is called imatinib (Gleevec). Imatinib was first developed for another type of leukemia. It was chronic myeloid leukemia. But we knew that acute lymphoblastic leukemia with BCR-ABL abnormality is lethal.

We had to do bone marrow transplant in every child with acute lymphoblastic leukemia. But now we have targeted cancer therapy. It is imatinib (Gleevec) or with other cancer medications combined with chemotherapy.

Now we can cure about 60% of children with acute lymphoblastic leukemia (ALL). We do not need to do a bone marrow transplant. We don't need bone marrow transplant anymore for many of them. 60% is not a lot.

Dr. Anton Titov, MD: We need to improve leukemia therapy further.

Dr. Shai Izraeli, MD: But that's an example of targeted cancer therapy. I just gave you the example of leukemia in children with Down syndrome. A common type of leukemia in children with Down syndrome is this. It is a Philadelphia-like chromosome leukemia.

These Philadelphia-like leukemias have abnormalities that may be targeted with specific cancer medications. I think we are just in the beginning of precision medicine age for child leukemia cure.