What’s New in Acute Lymphocytic Leukemia (ALL) Research?

Researchers are now studying the causes, genetics, and treatment of acute lymphocytic leukemia (ALL) at many medical centers, universities, and other institutions around the world.

Genetics of ALL

Scientists are making great progress in understanding how changes in the DNA (genes) inside normal bone marrow cells can cause them to develop into leukemia cells. A greater understanding of the gene changes that often occur in ALL cells is providing insight into why these cells become abnormal. As researchers have found more of these changes, it is becoming clear that there are many types of ALL. Each of these might have different gene changes that affect how the leukemia will progress and which treatments might be most helpful. Doctors are now learning how to use these changes to help determine a person’s outlook and whether they should receive more or less intensive treatment.

Perhaps even more important, this knowledge is now being used to help develop newer targeted therapy drugs against ALL. For example, targeted drugs such as imatinib (Gleevec) and dasatinib (Sprycel) are now used in treating ALL patients whose leukemia cells have the Philadelphia chromosome, and many other drugs targeting changes in ALL cells are now being developed.

Newer lab techniques are now helping researchers to identify and classify different types of ALL. Instead of looking at single genes, these tests can look at the patterns of many different genes in the cancer cells at the same time. This may add to the information that comes from the current lab tests.

This information may eventually allow more personalized treatment of ALL.

Finding minimal residual disease

Recently, highly sensitive tests have been developed to detect even the smallest amount of leukemia left after treatment (known as minimal residual disease, or MRD), even when there are so few leukemia cells left that they can’t be found by routine bone marrow tests.

For example, the polymerase chain reaction (PCR) test can identify even very small numbers of ALL cells in a sample, based on their gene changes. A PCR test can be useful in determining how completely the treatment has destroyed the ALL cells.

Doctors are now trying to determine what effect MRD has on a patient’s outlook, and how this might affect the need for further or more intensive treatment.

Improving treatment

Treatment for ALL can be very effective for some people, but it doesn't cure everyone (especially among adults), and it can often cause serious or even life-threatening side effects. Many studies are being done to find more effective and safer treatments for ALL.

Chemotherapy

Chemotherapy (chemo) is still the main treatment for nearly all cases of ALL. Studies are now being done to find the most effective combination of chemo drugs while limiting unwanted side effects. This is especially important in older patients, who often have a harder time tolerating current treatments.

New chemo drugs are also being developed and tested. For example, clofarabine (Clolar) is approved to treat childhood ALL and shows promise in early studies of adults with this disease. Nelarabine (Arranon) is a newer drug that can be used to treat T-cell ALL. Many other new drugs are also being studied.

Studies are also under way to determine whether patients with certain prognostic factors might benefit from more intensive chemo, and whether some ALL patients might not need as much treatment.

Sometimes, chemo might not work as well because the leukemia cells become resistant to it. Researchers are now looking at ways to prevent or reverse this resistance by using other drugs along with chemotherapy.

Stem cell transplants

Researchers continue to refine stem cell transplants to try to increase their effectiveness, reduce complications and determine which patients are likely to be helped by this type of treatment. Many studies are being done to try to help determine exactly when allogeneic, autologous, and mini-transplants might best be used.

Doctors are also studying donor leukocyte infusion (DLI) in people who have already received an allogeneic transplant and who relapse. In this technique, the patient gets an infusion of white blood cells (leukocytes) from the same donor who contributed the stem cells for the original transplant. The hope is that the cells will boost the new immune system and add to the graft-versus-leukemia effect. Early study results have been promising, but more research on this approach is needed.

Targeted therapy drugs

Newer targeted drugs that specifically attack some of the gene changes seen in ALL cells are now becoming an important part of treatment for some people with ALL. These drugs work differently from standard chemotherapy drugs.

Many other drugs targeting other changes in ALL cells are now being studied as well. Examples include:

• Proteasome inhibitors, such as bortezomib (Velcade), carfilzomib (Kyprolis), and ixazomib (Ninlaro)
• BCL-2 inhibitors, such as venetoclax (Venclexta)
• Syk inhibitors, such as entospletinib
• TORC1/2 inhibitors, such as sapanisertib

Immunotherapy

The goal of immunotherapy is to boost the body’s immune system to help fight off or destroy cancer cells.

Monoclonal antibodies

These drugs are man-made versions of immune system proteins (antibodies). They can be developed to attach only to certain proteins, such as those that are found on ALL cells.

Some monoclonal antibodies are already approved to treat ALL. These drugs are typically used if other treatments are no longer working, but they are now being studied for use earlier in the course of treatment as well (together with chemo).

Other monoclonal antibodies, such as rituximab (Rituxan) and ofatumumab (Arzerra), are already used to treat other blood disorders, and are now being studied for use against ALL.

Epratuzumab, a newer antibody, has also shown promise against ALL in early studies. Further studies are under way.

One promising treatment approach is to attach a chemo drug to a monoclonal antibody (known as an antibody-drug conjugate, or ADC). The antibody serves as a homing device to bring the chemo drug to the leukemia cell. Several such drugs have shown promise in early studies, and are now being tested in larger clinical trials.

Several other monoclonal antibodies to treat ALL are now being studied as well.

CAR T-cell therapy

This is a promising new way to get the immune system to fight leukemia. For this technique, immune cells called T cells are removed from the patient’s blood and altered in the lab so they have specific substances (called chimeric antigen receptors, or CARs) that will help them attach to leukemia cells. The CAR T cells are then grown in the lab and infused back into the patient’s blood, where they can now seek out the leukemia cells and attack them.

This technique has shown very promising results in early clinical trials against some types of advanced, hard-to-treat leukemias, and is now an option for some children and young adults with ALL. It is now being tested in older adults, too. With this treatment, some people have had very serious side effects, including very high fevers and dangerously low blood pressure in the days after it’s given. Doctors are learning how to manage these side effects.

Immune checkpoint inhibitors

An important part of the immune system is its ability to keep itself from attacking other normal cells in the body. To do this, it uses “checkpoints” – molecules on immune cells that need to be turned on (or off) to start an immune response. Cancer cells sometimes use these checkpoints to avoid being attacked by the immune system. But newer drugs that target these checkpoints hold a lot of promise as treatments. Some of these drugs are already being used to treat other types of cancer, and they are now being studied for use in ALL as well.