Tyrosine Kinase Inhibitors for Chronic Myeloid Leukaemia
Any drug or molecule for treatment of conditions in medicine undergoes an evolutionary process wherein there might be small alterations in their
structure which gives desirable properties in terms of activity, potency, stability and side effect profile.
These are, for purpose of recognition, categorized in terms of generations. With regards to CML we have the first generation TKIs in Imatinib while the 2nd generation TKIs available are Nilotinib and Dasatinib. Currently there is also the 3rd generation TKIs in the form of Ponatinib. The 2nd generation TKIs, Nilotinib and Dasatinib are much more potent molecules as compared to Imatinib.
They are also quite distinct from one another in terms of their side effect profile though comparable in terms of their effectiveness in treating newly diagnosed CML patients. They would also be useful when there is failure of adequate response to Imatinib which could result from mutations occurring in the BCR ABL protein bindingsites.
2nd generation TKIs are considered many times more potent than Imatinib in terms of their capability to bind with the BCR ABL protein and suppressing or blocking its activity. They have the capability to induce quicker and deeper responses in newly diagnosed patients with CML, which we today recognize as an important goal towards better control and the concept of treatment free remissions. It is perceived that these goals of sustained deep molecular or complete molecular responses are better achieved with 2nd generation TKIs. Under the circumstances there is an inclination towards using 2nd generation TKIs in newly diagnosed patients. However, there is no data that has conclusively shown that it has improved overall survival over Imatinib.
There is also a situation of using 2nd generation TKIs in newly diagnosed CML when there is indication that it is a high-risk disease, which the clinician ascertains through a scoring system called the SOKAL score. There is a suggestion that 2nd generation TKI are better suited when SOKAL risk score is high. Again 2nd generation TKIs are used when there is intolerance to Imatinib, which is rare but not uncommon.
Physician can use either niiotinib or dasatinib in first line. However there may be specific instances based on presence of comorbidities for using either. If the patient has pre-existent diabetes or peripheral vascular disease or any cardiac arrhythmia we may avoid niiotinib as first choice. Similarly if the patient has pulmonary problems, autoimmune disorder or hypertension etc physician may avoid dasatinib. Howeverthese are only relative.
Both molecules are completely different with different affinity for targets. Their activity in second line is sometimes dependent on presence or absence of specific mutations, if present, some of which are resistant to either niiotinib or dasatinib. These a re defined and determine the physicians choice of either.These molecules have their own unique toxicities too which have to be monitored and decisions taken thereafter for their conti nuance or cessation.
The patient on niiotinib can be switched to dasatinib and vice versa provided there is no specific mutation for the particular molecule for which the alternative has been used.
Niiotinib is available in the form of pale yellow capsules in strengths of 150mg and 200mg. The dosing is usually 300 to 400mg per day in divided doses. The intake of the medication has to be time bound and care should betaken to consume it with water one hour before or 2 hours after food. The capsules should not be opened ortampered with thus ensuring appropriate dosing.
The recommended starting dosage of Dasatinibfor chronic phase CML is 100 mg administered orally once daily. The recommended starting dosage of Dasatinib for accelerated phase CML, myeloid or lymphoid blast phase CML, or Ph+ ALL is 140 mg administered orally once daily. Tablets should not be crushed or cut; they should be swallowed whole.
Common side effects of Nilotinib
There could be a host of side effects that can occur with Nilotinib. These could be categorized as immediate or late. Some of them may be sporadic and self-limiting while some could be chronic and persistent. The immediate side effects include nausea, rash, non specific headache, feeling of lethargy and tiredness, itching, vomiting, intermittent diarrhea, cough, constipation, muscle and joint pain, nasal stuffiness and rhinitis, sneezing, sore throat. Sometimes there could be a drugfever and associated night sweats. Other more serious side effects could relate to aberrations leading to abnormal cardiac rhythm which can be potentially serious requiring attention.
This can particularly occur in presence of electrolyte disturbances, use of concomitant medications such as specific antihistamines and certain anti acidity drugs and even certain antibiotics. Nilotinib can also induce derangement in glucose metabolism resulting in elevated glucose levels and poor diabetic control in patients with pre-existing diabetis. It can cause low potassium and magnesium levels in the body resulting in symptoms of tiredness.
It can cause increase in the bilirubin levels which again may be self-limiting. During initial treatment nilotinib can rarely cause bone marrow suppression which manifests as low blood counts. The delayed side effects attributed to nilotinib have been peripheral vascular disease due to which there may be narrowing of vessels particularly in the extremities resulting in compromised blood flow. There have been concerns too about accelerated coronary narrowing especially in predisposed individuals having diabetis. Some patients rarely develop hypertension too after starting nilotinib. It is important to recognize these problems and take remedial measures and if required stop its use in presence of no remitting problems.
Serious side effects of Nilotinib
While any of the side effects if persistent can be serious, it is those related to the cardiovascular system that is of concern. Electrolyte imbalances and direct effects on the heart can result in abnormal rhythms which if not recognized is life threatening. The increase in sugar levels and poor control of diabetes induced or aggravated by Nilotinib can be detrimental if not controlled.
Liver dysfunction induced by nilotinib may require cessation of the medication to allow recovery.
The peripheral vascular disease resulting from long-term nilotinib ought to be recognized to prevent heart attacks and peripheral vascular (blood) insufficiency resulting in poor circulation to the extremities.
Any chest discomfort in the form of chest pain, palpitation (abnormal heart beat), and breathlessness should trigger a discussion with the doctor and attention by a medical team. Tinglingsensation in lower limbs, discoloration of the lower limbs and pain in the lower limbs on exertion would indicate circulatory compromise and need to be addressed.
It is generally considered a lifelong therapy. However, in the more recent understanding the concept of cessation after achieving a durable and sustained response for defined length of time have been explored in trial settings with promising results. However these aspects are to be considered only within the framework of a clinical study and not as routine practice.
The guidelines for monitoring a patient on 2nd generation TKIs is not any different from the general recommendation while on any TKI. The blood counts, biochemical parameters are routine assessments. Specific assessment would include cytogenetic response assessment on the bone marrow if possible.
More importantly the molecular monitoringfor decline of the BCR ABL protein is to be done at fixed intervals (ideally 3 months but at least every 6 months) in order to understand the ongoing response to therapy and also identifying any sluggish responses or loss of response.
Source: The Max Foundation
