Chronic myeloid leukemia (CML) is a clonal myeloproliferative syndrome with an estimated
incidence of 0.8-1 cases per 100,000 person-years in 2018 in France. CML is characterized
by the transformation of a pluripotent stem cell resulting in an increase in myeloid and
erythroid lineages and megakaryocytes in peripheral blood as well as myeloid hyperplasia
in the bone marrow.
In the absence of treatment, the disease, which begins in a chronic phase over a few
years, progresses to an acceleration phase, before reaching an acute phase, known as a
blast crisis, with a poor prognosis. This abnormal proliferation of white blood cells
results from the reciprocal translocation (exchange) between chromosomes 9 and 22. This
exchange brings two normally distinct genes into contact: the (breakpoint cluster region)
BCR gene and the abl gene (Tyrosine-protein kinase), which will form an abnormal gene
called "fusion Bcr-abl". This gene encodes a fusion protein with deregulated tyrosine
kinase activity that activates various mechanisms involved in cell multiplication.
Since the 1990s, the arrival of the first tyrosine kinase inhibitor (TKI), imatinib, has
radically changed patient management. Indeed, according to Public Health France, this
treatment has allowed the majority of patients to remain in the chronic phase for a long
time. Patient survival has therefore increased dramatically as the life expectancy of
patients with CML taking their treatment regularly approaches that of the general
population.
However, even though several generations of TKI have been developed, certain toxicities
may lead to discontinuation of treatment, or to a modification of the dose. Indeed, a
meta-analysis published in June 2020 shows that second and third generation of TKI
improve the major molecular response by 3 months, but are associated with a recrudescence
of thrombocytopenia, cardiovascular, pancreatic and hepatic events. First generation
imatinib therefore remains the best option for patients with co-morbidities despite the
frequent presence of headaches, digestive disorders, and cramps.
It has therefore always been customary to change the TKI or modify the prescribed doses,
while the side effects or ineffectiveness of these inhibitors could be explained by drug
interactions, or be related to the use of herbal medicine. Indeed, TKIs are metabolized
by the cytochrome P450 system. The activity of this cytochrome is not only different from
one person to another, but can also be affected by other treatments. For example, some
treatments will inhibit the activity of this cytochrome P450, increasing the exposure of
TKIs in plasma. The pharmacokinetics of the drug will therefore depend on these
concomitant treatments and their influence, among others, on cytochrome P450.
In addition, the median age at diagnosis is respectively 61 years for men and 62 years
for women. These patients are therefore often carriers of other chronic diseases and are
have multiple treatments.