Treatment of Chronic Myeloid LeukemiaMedical editor Tobias Gedde-Dahl d.y.
Oslo University Hospital
Chronic myeloid leukemia often starts with an indolent chronic phase which, before treatment with imatinib was introduced, progressed in 4–6 years via an accelerated phase to acute leukemia.
In the accelerated phase, the number of blasts and basophilic granulocytes increase in peripheral blood. The symptoms also increase in parallel and the condition is then more difficult to treat. This phase can last up to one year and then evolve into the blast phase (transformation). The disease profile is then acute leukemia where the immunophenotype can be lymphoblastic or myeloblastic. The prognosis is poor in these cases.
The tyrosine kinase inhibitor imatinib is the most effective medication for treatment of chronic myeloid leukemia. An allogeneic stem cell transplantation (myeloablative/non-myeloablative) is the only treatment method which, with assurance, can cure the disease.
Treatment with hydroxy urea (HU) gives longer survival than busulfan. Treatment with interferon-a gives approximately 6 months average extended survival compared to hydroxyl urea (HU) if administered at the disease debut.
- Control the disease on hematological, cytogenetic, and molecular levels.
- Maintain good quality of life.
Allogeneic stem cell transplantation
Using a family donor, about 70% of patients who receive transplantations (myeloablative/non-myeloablative) in the first chronic phase can be cured. With an unrelated donor, about 50% can be cured. The mortality associated with transplantations is, however, relatively high. This is the main objection against choosing this method as first line treatment.
Based on registry data, chances of survival and transplantation-related mortality can be estimated using the following independent risk factors:
- disease phase
- tissue compatibility between donor and patient
- sex of the donor (female donor to male patient is unfavorable)
- time from the diagnosis
In rare cases of chronic myeloid leukemia where there is a risk for disease progression and relatively low risk for transplantation complications, an allogeneic stem cell transplantation may be appropriate as first line treatment.
It is recommended that all CML patients are initially assessed as a potential candidate for a transplant, and that familial donor status is surveyed at the time of diagnosis (HLA typing), even if imatinib should be first line treatment.
Imatinib mesylate is an aminopyrimidine which shows relatively high specificity for inhibitation of BCR-ABL tyrosine kinase. It acheives this by competitively binding to the ATP receptor site on the BCR-ABL molecule.
Imatinib was registered in the EU in 2002 as first line treatment for newly diagnosed chronic myeloid leukemia in the chronic, accelerated, or blast phase.
Inhibition of BCR-ABL, in contrast to chemotherapy and interferon, directly attacks the disease pathogenesis, and is targeted therapy based on molecular biological knowledge. It is therefore also of great theoretical significance.
Imatinib does not kill leukemic stem cells and therefore does not eradicate the disease. Imatinib treatment is therefore in most cases, life-long treatment.
About 20% of chronic myeloid leukemia patients will either not tolerate imatinib, not respond with the desired effect (primary resistance), or the response will disappear (secondary resistance). These patients require alternative treatment. The high number of complete cytogenetic responses (CCyR) in the chronic phase of imatinib treatment has required more sensitive molecular monitoring with quantitative PCR techniques to evaluate the degree of response and early detection of loss of response.
Primary resistance may have multiple causes such as amplification of the BCR-ABL gene, constitutive activation of kinases farther down the signal pathways such as "SRC activation," loss of p53 or clonal evolution with other genetic changes.
In secondary resistance, it is known that in 50% of cases, there are point mutations which cause amino acid replacements in or at the imatinib binding site in the BCR-ABL molecule. These can either directly interfere with imatinib binding or cause conformational changes resulting in imatinib being unable to bind.
Some resistance mutations are treated by increasing the dosage to change the conditions for competition between ATP (adenosine triphosphate) and the medication. Other cases cannot be treated by an increase in dosage. There is also evidence that some mutations receive a great growth advantage since imatinib inhibits all unmutated CML cells. In these rare cases, imatinib treatment induces disease progression.
Most resistance mutations are present in CML subclones already at the time of diagnosis. Others are selected during treatment. Not all mutations are of clinical significance.
Secondary resistance is rare if imatinib is started at the time of diagnosis, but more frequent if the patient is in a late chronic phase when starting the treatment. It is therefore probably important to start imatinib treatment early.
Second generation BCR-ABL inhibitors
Based on BCR-ABL and imatinib's three-dimensional structure, other second-generation tyrosine kinase inbibitors have been constructed which are not as dependent on known mutations to be effective. The first two are already registered (dasatinib and nilotinib) for use in imatinib resistance/intolerance. These drugs are also not effective on all mutations, for example the T315I mutation.
New tyrosine kinase inhibitors are in trial.
- Provide information about the disease, treatment, and side effects.
- Risk stratification.
- Evaluate sibling donor situation.
- Consider treatment alternatives.
Multiple substances can inhibit the tyrosine kinase BCR-ABL, however, the inhibitor which is best explored is imatinib. Today, imatinib is the only tyrosine kinase inhibitor approved for first line treatment.
Imatinib is primary treatment for adult patients with Ph+ and/or BCR-ABL positive chronic myeloid leukemia.
The recommended dosage in the chronic phase is 400 mg/day.
If the patient is in a chronic phase and is still treated with hydroxy urea or interferon, without complete cytogenetic response, they should usually change to imatinib.
If the disease starts with an accelerated phase, a higher dosage of imatinib is given (600–800 mg/day). Patients who are < 55–60 years with a stem cell donor are appropriate for an allogeneic stem cell transplantation in this phase.
If the disease starts with a blast phase, the condition will most often be perceived as acute leukemia and treated accordingly. If BCR-ABL is detected or Ph+, it should be considered whether imatinib should be added or the dosage increased to 600-800 mg/day.
Development of blast crisis during imatinib treatment represents therapy failure. Dosage increase to 800 mg of a second-generation tyrosine kinase inhibitor possibly combined with conventional induction treatment for acute leukemia should be considered depending on the ABL mutation status and immunophenotype.
It is important to differentiate between the myeloid and lymphoid blast phase by utilizing microscopy supplemented with cytochemistry and immunophenotyping. The myeloid blast phase is more common than the lymphoid.
All treatment other than a stem cell transplantation has a short time limit and if the patient can be made fit for a transplantation, this should be the goal of the treatment.
An allogeneic stem cell transplantation in the blast phase is not included in the Norwegian stem cell program because international results are very poor. The patient must have reached a chronic phase for the transplantation to be considered since there is still a large risk of recurrence.
Poor response to imatinib or progression
For all forms of poor response or progression, an allogeneic stem cell transplantation is appropriate for patients < 55–60 years. Alternatively, second-generation tyrosine kinase inhibitors may be tried. Treatment should be discussed with a regional hospital. Liberal referral use is recommended for consideration by the Norwegian group for allogeneic stem cell transplantations.
Treatment with interferon (IFN) as monotherapy or combined with cytarabine extends survival by an average of 18 months. Today, this treatment is relevant in cases of intolerance to tyrosine kinase inhibitors or resistance in patients who are not suited for an allogeneic stem cell transplantation. For low risk of progression at the time of diagnosis or complete cytogenetic reponse to INF, 10 year survival is reported to be 70%. However, the problem is that few reach complete cytogenetic response with interferon treatment. Different combinations of imatinib and IFN and/or cytarabine are under evaluation in clinical studies. Interferon is the preferred treatment if it is necessary to treat the disease during pregnancy.
Hydroxyurea and busulfan
Hydroxyurea (HU) has replaced busulfan because it is more effective and easier to manage. HU can be chosen at diagnosis if there is a need for rapid reduction of leukocyte count with later transition to imatinib. Use of HU may also be indicated for elderly patients and patients with a weakened health status, as well as for palliative treatment with failing tyrosine kinase inhibitor treatment in patients who are not appropriate for a transplantation, interferon treatment, or clinical trial. The treatment goal is to bring the patient to a stable chronic phase. Busulfan is still relevant for a few patients where other therapies are not suitable.
The side effects from imatinib treatment have so far been mild.
The most common side effects are:
- hematological toxicity, anemia, neutropenia, and thrombocytopenia
- rise of transaminases
- peripheral edemas
Data beyond 8 year treatment is not available. However, there has been discussion of a possible influence on calcium and phosphate metabolism, worsening of heart failure, and development of urothelial malignancies.
Common side effects from high doses:
- hematological toxicity
Allergic rash, aphthous ulcers, and skin ulcerations occur. Macrocytosis and megaloblastic marrow is common.
Monitoring and treatment
Because not all patients tolerate or have consistently good effect of imatinib, and there exist alternative treatment regimens for some patients, careful monitoring is required. Based on present experience, definite achievements can be expected at certain time intervals. The treatment goals provide a basis for stratifying patients into optimal responders, sub-optimal responders and non-responders. These definitions may change over time as more experience is accumulated.
Today, hematological, cytogenetic, and molecular reponses are monitored:
- cytogenetics is performed twice a year on patients who have reached complete cytogenetic response, thereafter annually to catch possible changes, and clonal evolution
- molecular monitoring is performed every 3 months
- mutation analysis is performed if response is lost
Consensus at the current time in Europe is that the following response must be present for the patient not be categorized as a non-responder:
- 3 months – at least one complete hematological response
- 6 months – at least one cytogenetic response (< 95 % Ph+)
- 12 months – at least partial cytogenetic response (< 35 % Ph+)
- 18 months – at least one complete cytogenetic response (0 % Ph+)
Sub-optimal responses are also defined at these given points in time indicating critical evaluation of the treatment. Presence of unfavorable prognostic markers such as a high risk for progression at the time of diagnosis, detected deletions on derivative chromosome 9 and/or cytogenetic changes int he Ph+ clone are also emphasized in the response assessment.
If these are acceptable goals which should prompt change in treatment at the given point in time, they should be considered in connection with the patient's total situation and the available treatment alternatives.
Imatinib is considered a teratogen and should not be taken during conception or pregnancy.
Allogenic stem cell tranplantation with conventional conditioning usually causes permanent infertility. In these cases, sperm banking should be addressed at the time of diagnosis before the patient starts drug therapy.
Hydroxy urea probably does not cause permanent reduction of gonadal function but is assumed to be a teratogen.
In cases where the disease is diagnosed in connection with pregnancy, frequent follow-up with a hematologist and obstetrician is required throughout the pregnancy.