What is Chronic Myeloid Leukemia (CML)?

Chronic myeloid leukemia (or myelogenous leukemia, CML), is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of myeloid cells in the bone marrow and the accumulation of these cells in the blood.

CML is a bone marrow stem cell disorder. It is associated with a characteristic chromosomal translocation called the Philadelphia chromosome. In this translocation, parts of two chromosomes (the 9th and 22nd) switch places. As a result, part of the BCR ("breakpoint cluster region") gene from chromosome 22 is fused with the ABL gene on chromosome 9, creating the "fusion" gene bcr-abl, called a tyrosine kinase.

The tyrosine kinase is continuously active and does not require activation by other cellular mechanisms which normally regulate the division of cells. This leads to an uncontrolled multiplication of blood cells. Moreover, the bcr-abl protein inhibits the cells' DNA repair mechanisms, making the cell more susceptible to developing further genetic abnormalities.

With improved understanding of bcr-abl, targeted therapies like imatinib, nilotinib and dasatinib have been developed. These specifically inhibit the activity of the bcr-abl protein. These tyrosine kinase inhibitors are able to induce complete remissions in CML in about 80-90% of all patients treated in the first phase of the disease, the chronic phase.

What is so special about childhood CML?

In general, acute leukemias are most prevalent in children and are therefore often referred to as "childhood leukemias". The chronic forms of these leukemias, including Chronic Myeloid Leukemia (CML), are seen almost solely in adults. With the average age of diagnosis of CML being around 60 in western countries, CML in children is considered an ultra-rare condition. Incidence is unknown but estimations range around 20 new cases per year in Germany (80 million inhabitants) and 100 new cases in the USA. It accounts for less than 3% of all childhood leukemias and less than 10% of all CML cases. Incidence is suspected to be higher in developing countries, with The Max Foundation saying to have more than 2.000 pediatric CML patients in their database.

Long-term survival of pediatric patients with CML receiving hematopoietic stem cell transplantation from fully-matched related and unrelated donors has been reported between 60-75%, but is associated with significant morbidity. Imatinib and reduced intensity conditioning stem cell transplantation are two promising tools that offer potential for decreasing therapy associated morbidity for patients with CML. Recent publications by study groups indicate that stem cell transplant has been shifted to a 2nd line strategy also in pediatrics.

However, as CML is rare in children and young adults, most data on imatinib therapy is derived from adult studies where average inclusion age is around 45. In addition, there are certain issues like a negative impact on bone growth, uncertainty about long-term effects of TKI therapy, challenges of adherence to therapy, fertility and family planning issues as well as psycho-oncology that are more specific to CML in children and adolescents.