Q14: How are hematological adverse reactions to tyrosine kinase inhibitors (TKI) treated?
A: Hematological adverse reactions mainly refer to the abnormal blood routine after the application of TKI, mainly the decrease of white blood cells (WBC), red blood cells (RBC) and platelets (PLT), of which white blood cells mainly refer to neutrophils (NEU). Both first-generation (imatinib) and second-generation (nilotinib, dasatinib) TKI have a certain percentage of incidence of hematological adverse reactions, and their management principles are similar. Wei-Ming Lai, Department of Hematology, Wuhan Union Medical College Hospital
Here, please keep in mind that when adverse reactions occur, drug dose adjustment and related treatment must be carried out under the guidance of a doctor, and never take measures on your own to avoid delaying treatment.
The following is my personal clinical experience over the years, some of the views and drug instructions are different, now do a simple summary, share with colleagues, but also hope to help patients better understand the condition. Remember, because each patient’s condition is different, the specific medication measures should be taken, please be sure to communicate with your primary care physician!
A large amount of clinical data has confirmed that the efficacy is closely related to the dose of medication, so you should try to ensure the dose of medication, and do not reduce and stop the medication at will when you can ensure patient safety.
The following three aspects of adverse reactions are described in turn.
A) Management of neutropenia and principles of drug adjustment
Neutropenia will lead to an increased risk of infection (i.e., inflammation, fever) due to low immune function of the patient.
Therefore, when there is a drop in white blood cells in routine blood tests, attention should be paid immediately to the neutrophil count (NEU) among them. In general.
Risk of mild infection with NEU between 1.0 – 1.5 x 109/L
0.5 – 1.0×109/L, moderate risk of infection
< 0.5×109/L, called granulocyte deficiency, severe risk of infection
For patients in the chronic phase, the instructions for both imatinib and nilotinib call for patients to discontinue the drug at neutrophils < 1.0 × 109/L (i.e., moderate risk of infection) and not resume it until neutrophils ≥ 1.5 × 109/L (i.e., essentially no risk of infection).
My experience.
When a patient’s neutrophils are above 0.5×109/L, serious infections generally do not occur; clinically, it has been found that some patients with neutrophils even below 0.5×109/L do not develop infections, but they should be detected promptly and elevated as early as possible. Secondly, the duration of neutropenia is also an important factor in the occurrence of infection, so from this perspective, it also suggests the importance of close monitoring of blood count.
For a situation like 0.5×109/L < NEU < 1.0×109/L, my treatment is.
1) It is best not to reduce the dosage for the time being and add granulocyte colony-stimulating factor (a drug that specifically stimulates neutrophil growth), while doing routine blood tests every 2 days or so to monitor whether the neutrophil count rises.
(2) If the neutrophil count does not rise, consider reducing the dose, such as Imatinib from the initial 400mg/day to 300mg/day, Nilotinib from 800mg/day to 600mg/day, and Dasatinib from 100mg/day to 70mg/day.
For the case of NEU <0.5×109/L, my treatment was.
After the inability to recover with the addition of granulocyte colony-stimulating factor, discontinuation of the drug was then considered.
B) Management of thrombocytopenia and principles of medication adjustment.
Platelets (PLT) are an important component of the body’s hemostatic function, and if they decrease, the body’s hemostatic function is impaired. Generally speaking :
PLT ≥ 80 × 109 / L, can withstand major surgery
PLT ≥ 50×109/L, can withstand small and medium-sized surgery
PLT ≥ 30×109/L, no major bleeding risk in daily life in general
PLT < 20×109/L, risk of serious bleeding (e.g. intracranial bleeding).
In the instructions for TKI, patients using TKI in the chronic phase of chronic granulocytes are required to discontinue the drug when platelets are <50×109/L.
My experience.
1) 30×109/L < PLT < 50×109/L is recommended for dose reduction as the risk of bleeding is not significant. If Imatinib is reduced from initial 400mg/day to 300mg/day, Nilotinib from 800mg/day to 600mg/day, Dasatinib from 100mg/day to 70mg/day.
2) PLT < 30×109/L before considering discontinuation of the drug.
The above two experiences are for patients in the chronic phase, but for patients in the accelerated acute phase, because the disease has entered the advanced stage, the leukemia itself will cause blood cell decline, and because the leukemia cells are highly susceptible to drug resistance at this time, so it is even more important not to arbitrarily reduce the dosage and stop the drug. For patients in the accelerated acute phase, the principles of management are as follows.
In case of severe neutropenia or thrombocytopenia (neutrophils <0.5×109/L or platelets <10×109/L), bone marrow cytology or biopsy should be performed first.
1) If the hematocrit is found to be caused by leukemia (e.g., bone aspiration reveals that hyperplasia is active while leukemic cells remain high), it is recommended that the treatment be maintained for at least 2-3 weeks without dose reduction under the supportive therapy of colony-stimulating factor or platelet transfusion.
If hematocrit continues to decrease, then bone marrow cytology or biopsy should be performed again for re-evaluation.
(2) If hematocrit is found not to be leukemia-related (i.e., low myeloproliferation and no significant increase in leukemic cells), a dose reduction to imatinib 400 mg/day, nilotinib 600 mg/day, and dasatinib 100 mg/day under active supportive therapy may be considered.
If hematocrit persists for more than 2 weeks, continue dose reduction to the lowest dose (imatinib 300 mg/day, nilotinib 400 mg/day, dasatinib 70 mg/day) and discontinue if no improvement remains. Until neutrophils ≥ 0.5×109/L and platelets ≥ 20×109/L. Start again from the lowest dose.
(Note: The starting doses of TKI are imatinib 600mg/day, nilotinib 800mg/day and dasatinib 140mg/day).
C) Management of anemia and principles of drug modification.
Compared with neutropenia and thrombocytopenia, anemia is relatively less harmful to the organism and is better tolerated by the organism, and also the effect of red blood cell infusion is better, so dose reduction or discontinuation is generally not performed because of anemia. If the patient’s anemia is more severe (e.g., hemoglobin <60g/L), red blood cell infusion or erythropoietin injection can be applied to improve the red blood cell count.
Hematologic adverse reactions are generally more common in the early stages of drug administration. From the perspective of efficacy and safety, patients should always closely monitor the blood count under the guidance of a physician with clinical experience, make adjustments to the drug according to the results and treat side effects related to the drug, and try to ensure adequate dosage of the drug while ensuring safety.