What are the adverse effects of Imatinib for CML?
Leukemia lymphoma
Chronic granulocytic leukemia (chronic?myeloid?leukemia, CML) is a hematopoietic stem cell clonal myeloproliferative neoplasm with the hallmark Ph chromosome, t(9;22)(q34;q11), and the pathogenic basis is the translocation of c-abl located on 9q34 to the 3′ end of the bcr gene on 22q11, forming a bcr- abl fusion gene. This fusion gene encodes a bcr-abl fusion protein with high tyrosine kinase activity. Therefore, tyrosine kinase inhibitors (TKI) such as imatinib?mesylate (IM) can specifically inhibit the expression of bcr-abl, block cell signaling, inhibit the proliferation of bcr-abl positive cells, and induce cell growth arrest and apoptosis, and have been The adverse drug reactions caused by IM have gradually attracted attention, among which hematological adverse reactions are the most common. We retrospectively analyzed the occurrence of hematological adverse reactions in 435 patients with chronic phase CML treated with IM in our hospital, and analyzed the occurrence of hematological adverse reactions in each factor group to provide evidence for timely adjustment of medication and ensure the safety and effective use of medication.
I. Materials and methods
1.Case data
The clinical data of 435 patients with chronic phase of CML treated by IM from January 2013 to January 2015 were collected, including 203 males and 232 females with a median age of 46 years (8-78 years); 167 cases in the low-risk group (<0.8 score), 180 cases in the intermediate-risk group (0.8-1.2 score), and 88 cases in the high-risk group (>1.2 score) with Sokal score. The diagnostic and staging criteria were in accordance with the literature. All 435 patients were followed up by telephone and online registration system. Follow-up was performed until January 31, 2015, with a median follow-up time of 10 months (1 to 24 months).
2 , Treatment method
The starting dose of IM was 400?mg/d in adults and 260?mg/m2/day in children and adolescents. blood tests were performed once a week in the first month of treatment, once every two weeks in the second month, and thereafter the frequency of relevant tests (e.g., once every 2-3 months) was determined according to the patients’ clinical symptoms and needs. The drug was discontinued when grade III-IV hematologic adverse reactions occurred, and component blood transfusions and granulocyte colony-stimulating factor were given as supportive therapy; the drug was resumed at an absolute neutrophil count ≥1.5×109/L, platelet count ≥75×109/L, and hemoglobin ≥80g/L, and the dose was restored to 400?mg/d, and 260?mg/m2 per day for children and adolescents. when When critical values [absolute neutrophil count <1.0X109/L and/or platelet count <50x109/L] reappear, the dose after discontinuation is reduced to 300?mg/d for adults and 200?mg/m2 per day for children and adolescents. If Gua grade III-IV hematologic adverse reactions persist, the dose can be changed to a second-generation TKI, such as nilotinib or dasatinib.
3, evaluation criteria
The evaluation of hematological adverse reactions is based on the CTCAE criteria of the National Cancer Institute.
Table 1
4 . Statistical methods
SPSS?17.0 software was used for statistical analysis. χ2 test was used to compare the incidence of hematological adverse reactions among the factor groups, and the difference was considered statistically significant at P<0.05.
II. Results
1. Occurrence of hematological adverse reactions
By the follow-up deadline, 361 (83.0%) of 435 patients in the chronic phase had normal hematology and 74 (17.0%) had hematological adverse reactions. 61 (14.0%) had neutropenia, 24 males and 37 females, with a median age of 43 years, of which 9 (14.8%) were grade III and IV. 60 (13.8%) had thrombocytopenia, 28 males and 32 females, with a median age of 43 years. 28 cases, 32 cases in women, median age 43 years, including 11 cases of grade III and IV (18.3%). 50 cases (11.5%) had anemia, 21 cases in men, 29 cases in women, median age 45 years, including 5 cases of grade III and IV (310.0%). 33 cases (7.6%) had complete hematocrit reduction. Hematological adverse reactions occurred mostly in 2~3 weeks after treatment, the earliest of which the hemogram dropped after 1 week of drug administration, reached a trough in 3~4 weeks, and gradually returned to positive after 4~6 weeks.
2. Follow-up treatment and efficacy of patients whose blood picture did not recover after stopping the drug
In 6 patients, the blood picture continued to be in grade III and IV myelosuppression after discontinuation of the drug. For these patients, IM was replaced with second-generation TKI such as nilotinib and dasatinib on the basis of symptomatic supportive therapy such as component transfusion and granulocyte colony stimulating factor, and 5 of them recovered after drug replacement.
3 . Factors influencing the occurrence of hematological adverse reactions
The differences in the incidence of hematological adverse reactions were statistically significant (all p<0.05) among patients in the group of nine factors: duration of disease before treatment, spleen size, Sokal score, whether interferon was used, fusion gene, chromosome, whether complete cytogenetic remission (CCyR) was obtained, whether major molecular response (MMR) was obtained, and Karnofsky score, and the differences in the incidence of hematological adverse reactions among patients in the group of nine factors: age, sex, body mass There was no statistically significant difference in the incidence of hematological adverse reactions among patients in the groups of age, sex, body mass index (BMI), and whether they smoked and drank alcohol (all p>0.05).
III. Discussion
IM is a first-generation TKI drug that competitively targets the inhibition of bcr-abl tyrosine kinase, resulting in high hematological and cytogenetic response rates in CML patients, and has now become the first-line treatment of choice for patients in the chronic phase of CML. Because tyrosine kinase is involved in the metabolism of many tissues in the body, and the inhibition of tyrosine kinase by IM is non-specific, i.e., it inhibits all tyrosine kinases in the body except those in bcr-abl’, it can cause adverse reactions in various systems of the body, mainly divided into hematological adverse reactions and non-hematological adverse reactions. Hematologic adverse reactions are common in IM treatment of CML and are mainly characterized by neutropenia, thrombocytopenia and anemia. Non-hematological adverse reactions mainly include digestive system abnormalities such as nausea, vomiting and diarrhea, skin and subcutaneous tissue abnormalities such as rash and erythrodermatitis, and fluid retention such as edema, etc. Although adverse reactions caused by IM are very common, they are mostly mild to moderate and are tolerated by the majority of patients and generally do not require drug dose adjustment or discontinuation.
In this study, we retrospectively analyzed 435 patients with chronic phase CML treated with IM, of whom 361 (83.0%) had normal hematology and 74 (17.0%) had hematologic adverse reactions, including 61 (14.0%) neutropenia, 60 (13.8%) thrombocytopenia, and 50 (11.5%) anemia. The hematological adverse reactions occurred mostly in 2-3 weeks after treatment, with the earliest one being a drop in blood picture after 1 week of drug administration, reaching a trough in 3-4 weeks, and gradually returning to normal after 4-6 weeks, which is consistent with the reports in the domestic literature.
The occurrence of hematological adverse reactions may be due to the following reasons.
(1) After taking IM, bcr-abl+ cells are inhibited, the old pathological hematopoietic balance is broken, and the new balance is not yet established, so the blood cells show a transient decrease, which mostly occurs in the first few weeks of treatment and is a reflection of the treatment effect, and the blood cells can gradually rebound with the establishment of the new normal hematopoietic balance.
(2) IM inhibits c-kit gene and/or Src and related kinases while suppressing bcr-abl+ cells. c-kit gene plays an important role in the growth and development of normal hematopoietic cells, and Src and related kinases are key signal transduction factors in the normal hematopoietic process, thus leading to inhibition of normal hematopoietic stem cell growth and lower blood cells.
(3) Higher leukemic load, deficiency in the number or function of normal hematopoietic clones leads to hematocrit reduction.
(4) Patients with hematologic adverse reactions late in treatment may still have one or more lineages of hematocrit reduction, although they remain in the chronic phase with bone marrow morphology suggesting active or extremely active proliferation due to reasons related to drug resistance or disease progression after taking IM, but the bone marrow is not in complete remission.
Therefore, we believe that in the early stage of IM treatment of CML, if grade I or II hematological adverse reactions occur, the drug can be continued, and if grade III-IV hematological adverse reactions occur, the drug needs to be reduced or stopped, and if necessary, it can be combined with supportive therapy such as Yi Xuesheng capsule, Diyu Boosting Tablets, component blood transfusion and granulocyte colony-stimulating factor, and the hemogram tends to stabilize after 4-6 weeks of treatment. In case of serious hematological adverse reactions in the late stage of IM treatment of CML, bone marrow morphology, cytogenetics, molecular biology and TKI resistance genes and other related examinations are required to clarify the disease stage and understand the myeloproliferative situation, and if necessary, replace with second-generation TKI such as nilotinib.