Gentle Treatment for Leukemia

Leukemia is the most common type of cancer in children and adolescents. Around one-third of young cancer patients, who in Switzerland are treated at various hospitals including the University Children’s Hospital Zurich, suffer from leukemia. This is also the type of cancer that has seen the greatest treatment success.

“A few decades ago, a leukemia diagnosis was almost like a death sentence,” says Jean-Pierre Bourquin, “now, 90% of all cases can be cured.” Through his research, the pediatric oncologist and head of the National Center of Competence in Research (NCCR) Children & Cancer has played a key part in this success.

The most common form of cancer in children is acute lymphoblastic leukemia (ALL), accounting for around 60 cases a year in Switzerland. In ALL, the white blood cells – lymphocytes – become malignant, and multiply uncontrollably throughout the body. This hinders the production of healthy blood. The disease, which can also occur in adults, is often caused by genetic alterations. The fusion of two chromosomes creates new, abnormal genes that disrupt normal blood cell production.

Jean-Pierre Bourquin has been researching ALL extensively for several decades to gain new insights and develop better treatments. A team of researchers led by Bourquin was able to show how pathogenic genes are “switched on”. In a study, they identified over a hundred proteins that cause genes to be activated when they shouldn’t be, including 11 factors that are crucial to the development of leukemia. If these factors are missing, malignant blood cells do not form. Such insights from basic research provide important impetus for the development of new therapies.

Medicine celebrated its first successes in leukemia treatment in the 1960s, when researchers started to combine different medications to tackle blood cancer more effectively. This “combination therapy” was modeled on the successful treatment of tuberculosis with a mix of medications. “That was the breakthrough,” says Jean-Pierre Bourquin.

This approach has since been continually refined and adapted to the individual needs of young patients. “Through more accurate diagnoses, more intensive therapies and increasingly sophisticated risk assessment for ALL, we have made great gains in survival free of blood cancer,” says Bourquin, “but at the cost of significant toxicity and corresponding long-term effects.”

This is because conventional chemotherapies can cause issues such as bone damage and learning or concentration disorders, meaning that around one-fifth of patients require long-term medical care after their leukemia has been cured. Pediatric oncologist Bourquin therefore says: “It’s no longer about how we can cure the disease, but rather how we can treat it as gently as possible and avoid serious long-term effects.” He assumes that many of the young patients could undergo less intensive treatment if it were possible to predict more accurately who would respond well to a therapy.

The guiding principle here is as little as possible and as much as necessary. The new NCCR Children & Cancer aims, among other things, to help optimize therapy through in-depth studies. One of the key objectives of the project is to diagnose individual cases of cancer even more accurately in order to pinpoint the optimal treatment for every patient and therefore minimize the long-term effects. “In an ideal world, leukemia would be treated without chemotherapy,” says Bourquin.

It is also about finding new ways to treat children with particularly aggressive forms of blood cancer more successfully, as some particularly severe cases of leukemia do not respond to any conventional therapies. In such cases, affected children can be treated with a stem cell transplant, whereby the diseased bone marrow is replaced by healthy stem cells, usually from a family member, after high-dose chemotherapy.

A newer, more promising and gentler alternative to traditional chemotherapies are treatments that train patients’ immune systems to target and destroy leukemia cells.

In CAR T-cell immunotherapy, for example, the patient’s own body cells are genetically modified so that they attack and destroy cancer cells. The therapy was developed in the United States specifically for children with lymphoblastic leukemia and has also been licensed for use in Switzerland since 2018. Jean-Pierre Bourquin was one of the first doctors to use the therapy in Switzerland.

The advantage of such treatments is that they are more targeted than traditional chemotherapies and therefore cause less damage to the body. But however encouraging that prospect sounds, here, too, a number of obstacles need to be overcome. Previous experience has shown that many of the young patients initially respond well to an immunotherapy, but relapses occur in around half of cases. And, notes the pediatric oncologist, it is not yet known whether the cancer will return several years after successful immune therapy. The relevant longitudinal data is still lacking.

So it won’t be possible to dispense with chemotherapy entirely in the near future. “But,” says Jean-Pierre Bourquin, “we all firmly believe that for leukemia with favorable biology, we should use immunotherapies from the outset to significantly reduce standard chemotherapy. We know from early clinical experience that around half of patients would be cured with much less chemotherapy than today. And we now have good biomarkers to rapidly identify these types of leukemia during the initial diagnosis.”

A major consortium is needed that is willing to assess and take the risk of a significant targeted reduction, he maintains. The researchers are therefore working with international partners to improve therapies so that they strike the delicate balance between being effective and being easier on the body. In this way, they are increasing young patients’ chances of a future that is as symptom-free as possible following successful leukemia treatment. Because, in the best case, they still have their whole lives ahead of them.